Inhibitors of PI3K-Delta and Methods of Their Use and Manufacture

ABSTRACT

The invention is directed to Compounds of Formula I: and pharmaceutically acceptable salts or solvates thereof as well as methods of making and using the compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalApplication No. 61/382,873, filed Sep. 14, 2010, which is incorporatedherein by reference.

FIELD OF THE INVENTION

This invention relates to the field of protein kinases and inhibitorsthereof. In particular, the invention relates to inhibitors of PI3Kdelta, and methods of their use.

BACKGROUND OF THE INVENTION

Phosphoinositide 3-kinases (PI3ICs) are heterodimeric enzymes thatutilize both lipid and protein kinase activity to regulate numerouslipid signaling pathways that are responsible for coordinating a broadrange of cellular activities including cell survival, proliferation, anddifferentiation as well as inflammatory responses. The critical role ofPI3ICs in these myriad important cellular processes make them a veryattractive target for pharmaceutical intervention. The class of PI3Ksrelevant to this disclosure catalyze the phosphorylation ofphosphatilyl-inositol (4,5)-bisphosphate (Ptlns(4,5)P₂ or PIP₂) on the3-hydroxyl group of the inositol ring to produce the signaling moleculephosphatilyl-inositol (3,4,5)-triphosphate (Ptlns(3,4,5)P₃ or PIP₃).

After extensive studies on the physiological role of the PI3K deltaisoform in disease, PI3K delta is implicated in a large number ofimmunological, inflammatory and cell regulation dysfunctions. Initialstudies have focused its role in immune and inflammatory pathologies.PI3K delta plays a significant role in the development, differentiation,proliferation and effector function of B-cells and T-cells. PI3K deltaknock-in mice (D910A/D910A) have shown impaired or diminishedproliferative T-cell responses and chemokine production when stimulatedwith T-cell receptor specific antigens. Moreover, these PI3K deltaexpressing animals demonstrate poor T-cell independent antibodyresponses concomitant with poor development of germinal centers in thespleen, lymph nodes and Peyer's patches and lymphoid hyperplasia afterimmunization. Inhibition of PI3K delta function also leads todysfunctional homing by T-cells to sites of inflammation. PI3K deltaactivity has also been implicated in Treg cell control. PI3Kdelta^((D910A/D910A)) mice have Treg cells that fail to: 1.) suppressthe proliferation of CD4⁺ CD25⁻ T-cells in vitro as well as Treg cellsfrom wild-type animals; 2.) produce detectable levels of theanti-inflammatory cytokine IL-10; and 3.) protect against experimentalcolitis.

The effects of PI3K delta on B-cells are no less significant. Micelacking p110 delta catalytic activity have reduced numbers of Bl andmarginal zone (MZ) B cells, reduced levels of serum immunoglogulins, andrespond poorly to immunization with a thymus-independent antigen and aredefective in their primary and secondary responses to thymus dependentantigens. Inhibition of PI3K delta via use of PI3K delta selectiveinhibitors have shown inhibition of B-cell receptorinduced B cellproliferation, and increased class-switch recombination. and defects inB-cell chemotaxis.

Experimental observations that PI3K delta may play a significant role inmediating the proinflammatory role of non-lymphoid hematopoetic cellshave come from studies involving hematopoietic immune cells such asneutrophils, macrophages, dendritic cells, mast cells and eosinophils.For example, PI3K delta is required for neutrophil spreading andpolarization, regulation of neutrophil migration, mast celldegranulation and among many others. A review of the important roles ofPI3K delta in innate and adaptive immune responses, has generatedintense investigation of the role of PI3K delta in immune diseases suchas allergy, asthma, autoimmune diseases, and inflammation.

While a significant portion of the published scientific literature hasfocused on immune diseases, such as inflammation, autoimmune disease andthe like, an attractive and productive area for investigation includesthe role of PI3K delta in cancer. Experimental models have alreadyprovided for putative roles of PI3K alpha and PI3K beta in malignantcellular processes, including: (i) overexpression is capable of inducingtransformation in experimental models; (ii) involvement in cellproliferation and tumor angiogenesis; (iii) involvement in Ras-inducestransformation and oncogenesis (iv) activating mutations in the helicaland kinase domains in breast and colon tumors; and (v) transformationinduced by PTEN inactivation in vitro and in vivo.

As with PI3K alpha and PI3K beta, PI3K delta also induces oncogenictransformation in culture. When PI3K delta is introduced into chickenembryo fibroblasts (CEFs) with an avian retroviral vector, distinct fociform within ten days. When D910A kinase inactive PI3K delta isintroduced into CEFs, no focus formation is observed indicating thattransformation requires an active catalytic domain. As was observed foran oncogenic variant of PI3K alpha (H1047R), CEFs infected with PI3Kdelta showed constitutive activation of Akt at a level similar to PI3Kalpha, even in serum starved conditions. For at least the reasonsprovided above, there is a need for selective PI3K delta inhibitors thatcan be used to prevent, treat or ameliorate PI3K delta mediateddiseases, particularly in the fields of cancer, inflammation andautoimmune diseases.

SUMMARY OF THE INVENTION

The following only summarizes certain aspects of the invention and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below. All references cited inthis specification are hereby incorporated by reference in theirentirety. In the event of a discrepancy between the express disclosureof this specification and the references incorporated by reference, theexpress disclosure of this specification shall control.

We recognized the important role of PI3K, particularly PI3K delta, inbiological processes and disease states and, therefore, realized thatinhibitors of these protein kinases would be desirable. Accordingly, theinvention provides compounds that inhibit, regulate, and/or modulatePI3K delta that are useful in the treatment of various cancers,autoimmune diseases, inflammatory diseases in mammals. This inventionalso provides methods of making the compounds, methods of using suchcompounds in the treatment diseases, particularly hyperproliferativediseases, in mammals, especially humans, and to pharmaceuticalcompositions containing such compounds.

A first aspect of the invention provides a compound of Formula I:

or a stereoisomer or mixture of stereoisomers thereof, optionally as apharmaceutically acceptable salt thereof, wherein:

-   A is N, C—H, or C—OH;-   B is C—H or N;-   E is absent or is C—R⁴;-   G is S C—H, or C—R³;-   J is C or N when A is C—H or C—OH, or J is C when A is N;-   X is absent or is NH or is optionally substituted N—(C₁-C₆)alkyl;-   Y is absent or is optionally substituted (C₁-C₆)alkylene wherein up    to two carbon atoms of the (C₁-C₆)alkylene are replaced by O, NH,    N—(C₁-C₆)alkyl, —NH—(C═O)—, —N(C₁-C₆)allcyl-(C═O)—, or —(C═O)—;-   Q is absent or is (C₁-C₆)alkylene;-   Z is absent or is NH, N(C₁-C₆)alkyl, NH(C₁-C₆)alkylene, —NH—(C═O)—,    —N(C₁-C₆)alkyl-(C═O)—, S, SO, SO₂, or O;-   R¹ is halo, hydroxy, cyano, optionally substituted aryl, optionally    substituted heteroaryl, optionally substituted heterocycloalkyl,    optionally substituted (C₁-C₆)alkyl, optionally substituted    (C₁-C₆)alkoxy, (C₁-C₆)alkyl-OH, NH₂, —NH—((C₁-C₆)alkyl)₂,    —NH—(C═O)—R⁵, —(C═O)NR⁶R⁷, or —NH—(SO₂)—R⁸;-   R² is NH₂, optionally substituted cycloalkyl, optionally substituted    heterocycloalkyl, or optionally substituted heteroaryl,-   R³ at each occurrence is independently halo, cyano, optionally    substituted (C₁-C₆)alkyl, or (C₁-C₆)alkoxy;-   R⁴ is H or optionally substituted (C₁-C₆)alkyl;-   R⁵ is H, optionally substituted (C₁-C₆)alkyl, optionally substituted    cycloalkyl, optionally substituted heterocycloalkyl, optionally    substituted aryl, or optionally substituted heteroaryl;-   R⁶ and R⁷ are each independently H, optionally substituted    (C₁-C₆)alkyl, optionally substituted cycloalkyl, optionally    substituted heterocycloalkyl, optionally substituted aryl,    optionally substituted heteroaryl, or R⁶ and R⁷, together with the    atoms to which they are attached, can be taken together to form an    optionally substituted 3, 4, 5, 6, or 7-membered ring;-   R⁸ is optionally substituted (C₁-C₆)alkyl, optionally substituted    cycloalkyl, optionally substituted heterocycloalkyl, optionally    substituted aryl, or optionally substituted heteroaryl.

In a second aspect, the invention provides a pharmaceutical compositionwhich comprises 1) a compound of Formula I or a single stereoisomer ormixture of isomers thereof, optionally as a pharmaceutically acceptablesalt thereof and 2) a pharmaceutically acceptable carrier, excipient, ordiluent.

In a third aspect, the invention provides a method of inhibiting the invivo activity of PI3K delta, the method comprising administering to apatient an effective IPI3K delta-inhibiting amount of a Compound ofFormula I or a single stereoisomer or mixture of stereoisomers thereof,optionally as a pharmaceutically acceptable salt or solvate thereof orpharmaceutical composition thereof.

In a fourth aspect, the invention provides a method for treating adisease, disorder, or syndrome which method comprises administering to apatient a therapeutically effective amount of a compound of Formula I ora single stereoisomer or mixture of isomers thereof, optionally as apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof Formula I or a single stereoisomer or mixture of isomers thereof,optionally as a pharmaceutically acceptable salt or solvate thereof, anda pharmaceutically acceptable carrier, excipient, or diluent.

In a fifth aspect, the invention provides a process for making acompound of Formula II-B, comprising:

(a) converting a compound of formula II-1 to a compound of formula II-2via reduction to the alcohol and converion of the alcohol to the thehalide, wherein X¹ is halo;

(b) converting a compound of formula II-2 to a compound of formula II-3via azide formation and subsequent reduction;

(c) converting a compound of formula II-3 to a compound of formula II-4via reaction with R²-X², wherein X² is halo

(d) converting a compound of formula II-4 to a compound of formula II-Bvia reaction with CH₃NH—Y—R¹;

In a sixth aspect, the invention provides a process for making acompound of Formula II-A, comprising:

(a) converting the carboxylic acid of formula II-5 to an amide offormula II-6;

(b) converting a compound of formula II-6 to a compound of formula II-7via treatment with 2-haloacetyl chloride, wherein X¹ is halo;

(c) converting a compound of formula II-7 to a compound of formula II-8via via azide formation and subsequent reduction;

(d) converting a compound of formula II-8 to a compound of formula II-Avia reaction with R2-CO₂H;

DETAILED DESCRIPTION OF THE INVENTION

The following abbreviations and terms have the indicated meaningsthroughout:

Abbreviation Meaning AcOH acetic acid br broad ° C. degrees Celsius concconcentrated d doublet dd doublet of doublet dt doublet of triplet DCMdichloromethane DIEA or DIPEA N,N-di-isopropyl-N-ethylamine DMAN,N-dimethylacetamide DME 1,2-dimethoxyethane DMF N,N-dimethylformamideDMSO dimethyl sulfoxide dppf 1,1′-bis(diphenylphosphano)ferrocene EIElectron Impact ionization equiv equivalents g gram(s) GC/MS gaschromatography/mass spectrometry h or hr hour(s) HATU2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate HPLC high pressure liquid chromatography L liter(s)LC/MS liquid chromatography/mass spectrometry M molar or molarity mMultiplet MeOH methanol mg milligram(s) MHz megahertz (frequency) minminute(s) mL milliliter(s) μL microliter(s) μM micromolar μmolmicromole(s) mM Millimolar mmol millimole(s) mol mole(s) MS massspectral analysis Ms mesyl N normal or normality nM Nanomolar NMRnuclear magnetic resonance spectroscopy q Quartet quant quantitative rtRoom temperature s Singlet t or tr Triplet THF tetrahydrofuran Ts tosyl

The symbol “—” means a single bond, “═” means a double bond, “≡” means atriple bond, “

” means a single or double bond. The symbol “

” refers to a group on a double-bond as occupying either position on theterminus of a double bond to which the symbol is attached; that is, thegeometry, E— or Z—, of the double bond is ambiguous. When a group isdepicted removed from its parent Formula , the “

” symbol will be used at the end of the bond which was theoreticallycleaved in order to separate the group from its parent structuralFormula.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to have hydrogen substitutionto conform to a valence of four. For example, in the structure on theleft-hand side of the schematic below there are nine hydrogens implied.The nine hydrogens are depicted in the right-hand structure. Sometimes aparticular atom in a structure is described in textual Formula as havinga hydrogen or hydrogens as substitution (expressly defined hydrogen),for example, —CH₂CH₂—. It is understood by one of ordinary skill in theart that the aforementioned descriptive techniques are common in thechemical arts to provide brevity and simplicity to description ofotherwise complex structures.

If a group “R” is depicted as “floating” on a ring system, as forexample in the Formula:

then, unless otherwise defined, a substituent “R” may reside on any atomof the ring system, assuming replacement of a depicted, implied, orexpressly defined hydrogen from one of the ring atoms, so long as astable structure is formed.

If a group “R” is depicted as floating on a fused or bridged ringsystem, as for example in the Formula e:

then, unless otherwise defined, a substituent “R” may reside on any atomof the fused or bridged ring system, assuming replacement of a depictedhydrogen (for example the —NH— in the Formula above), implied hydrogen(for example as in the Formula above, where the hydrogens are not shownbut understood to be present), or expressly defined hydrogen (forexample where in the Formula above, “Z” equals ═CH—) from one of thering atoms, so long as a stable structure is formed. In the exampledepicted, the “R” group may reside on either the 5-membered or the6-membered ring of the fused or bridged ring system.

When a group “R” is depicted as existing on a ring system containingsaturated carbons, as for example in the Formula:

where, in this example, “y” can be more than one, assuming each replacesa currently depicted, implied, or expressly defined hydrogen on thering; then, unless otherwise defined, where the resulting structure isstable, two “R's” may reside on the same carbon. In another example, twoR's on the same carbon, including that carbon, may form a ring, thuscreating a spirocyclic ring structure with the depicted ring as forexample in the Formula:

“Acyl” means a —C(O)R radical where R is alkyl, haloalkyl, alkenyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, or heterocycloalkylalkyl, as defined herein, e.g.,acetyl, trifluoromethylcarbonyl, or 2-methoxyethylcarbonyl, and thelike.

“Acylamino” means a —NRR′ radical where R is hydrogen, hydroxy, alkyl,or alkoxy and R′ is acyl, as defined herein.

“Acyloxy” means an —OR radical where R is acyl, as defined herein, e.g.cyanomethylcarbonyloxy, and the like.

“Administration” and variants thereof (e.g., “administering” a compound)in reference to a compound of the invention means introducing thecompound of the compound into the system of the animal in need oftreatment. When a compound of the invention or prodrug thereof isprovided in combination with one or more other active agents (e.g.,surgery, radiation, and chemotherapy, etc.), “administration” and itsvariants are each understood to include concurrent and sequentialintroduction of the compound or prodrug thereof and other agents.

“Alkenyl” means a means a linear monovalent hydrocarbon radical of twoto six carbon atoms or a branched monovalent hydrocarbon radical ofthree to 6 carbon atoms which radical contains at least one double bond,e.g., ethenyl, propenyl, 1-but-3-enyl, and 1-pent-3-enyl, and the like.

“Alkoxy” means an —OR group where R is alkyl group as defined herein.Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like.

“Alkoxyalkyl” means an alkyl group, as defined herein, substituted withat least one, specifically one, two, or three, alkoxy groups as definedherein. Representative examples include methoxymethyl and the like.

“Alkoxycarbonyl” means a —C(O)R group where R is alkoxy, as definedherein.

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to 6 carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, butyl (including all isomeric forms), or pentyl (including allisomeric forms), and the like.

“Alkylamino” means an —NHR group where R is alkyl, as defined herein.

“Alkylaminoalkyl” means an alkyl group substituted with one or twoalkylamino groups, as defined herein.

“Alkylaminoalkyloxy” means an —OR group where R is alkylaminoalkyl, asdefined herein.

“Alkylcarbonyl” means a —C(O)R group where R is alkyl, as definedherein.

“Alkylene” means an optionally substituted straight or branched chaindivalent hydrocarbon radical, preferably having from one to ten carbonatoms, unless specified otherwise. Examples of “alkylene” as used hereininclude, but are not limited to, methylene, ethylene, n-propylene,n-butylene, and the like.

“Alkylsufonyl” means an —S(O)₂R group where R is alkyl, as definedherein.

“Alkylsulfonylalkyl” means an alkyl group, as defiled herein,substituted with at least one, preferably one or two, alkylsulfonylgroups, as defined herein.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three to 6carbon atoms which radical contains at least one triple bond, e.g.,ethynyl, propynyl, butynyl, pentyn-2-yl and the like.

“Amino” means —NH₂.

“Aminoalkyl” means an alkyl group substiuted with at least one,specifically one, two or three, amino groups.

“Aminoalkyloxy” means an —OR group where R is aminoalkyl, as definedherein.

“Aminocarbonyl” means a —C(O)NH2 group.

“Alkylaminocarbonyl” means a —C(O)NHR group where R is alkyl as definedherein.

“Aryl” means a monovalent six- to fourteen-membered, mono- orbi-carbocyclic ring, wherein the monocyclic ring is aromatic and atleast one of the rings in the bicyclic ring is aromatic. Unless statedotherwise, the valency of the group may be located on any atom of anyring within the radical, valency rules permitting. Representativeexamples include phenyl, naphthyl, and indanyl, and the like.

“Arylalkyl” means an alkyl radical, as defined herein, substituted withone or two aryl groups, as defined herein, e.g., benzyl and phenethyl,and the like.

“Arylalkyloxy” means an —OR group where R is arylakyl, as defiendherein.

“Cyanoalkyl” means an alkyl group, as defined herein, substituted withone or two cyano groups.

“Cycloalkyl” means a monocyclic or fused or bridged bicyclic ortricyclic, saturated or partially unsaturated (but not aromatic),monovalent hydrocarbon radical of three to ten carbon ring atoms. Unlessstated otherwise, the valency of the group may be located on any atom ofany ring within the radical, valency rules permitting. One or two ringcarbon atoms may be replaced by a —C(O)—, —C(S)—, or —C(═NH)— group.More specifically, the term cycloalkyl includes, but is not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl,cyclohex-3-enyl, or (1r,3r,5R,7R)-tricyclo[3.3.1.1^(3,7)]decan-2-yl, andthe like.

“Cycloalkylalkyl” means an alkyl group substituted with at least one,specificallyone or two, cycloalkyl group(s) as defined herein.

“Dialkylamino” means a —NRR′ radical where R and R′ are alkyl as definedherein, or an N-oxide derivative, or a protected derivative thereof,e.g., dimethylamino, diethylamino, N,N-methylpropylamino orN,N-methylethylamino, and the like.

“Dialkylaminoalkyl” means an alkyl group substituted with one or twodialkylamino groups, as defined herein.

“Dialkylaminoalkyloxy” means an —OR group where R is dialkylaminoalkyl,as defined herein. Representative examples include2-(N,N-diethylamino)-ethyloxy, and the like.

“Dialkylaminocarbonyl” means a —C(O)NRR′ group where R and R′ are alkylas defined herein.

“Halogen” or “halo” refers to fluorine, chlorine, bromine and iodine.

“Haloalkoxy” means an —OR′ group where R′ is haloalkyl as definedherein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.

“Haloalkyl” mean an alkyl group substituted with one or more halogens,specifically 1, 2, 3, 4, 5, or 6 halo atoms, e.g., trifluoromethyl,2-chloroethyl, and 2,2-difluoroethyl, and the like.

“Heteroaryl” means a monocyclic or fused or bridged bicyclic monovalentradical of 5 to 14 ring atoms containing one or more, specifically one,two, three, or four ring heteroatoms where each heteroatom isindependently —O—, —S(O)_(n)—(n is 0, 1, or 2), —NH—, —N═, or N-oxide,with the remaining ring atoms being carbon, wherein the ring comprisinga monocyclic radical is aromatic and wherein at least one of the fusedrings comprising the bicyclic radical is aromatic. One or two ringcarbon atoms of any nonaromatic rings comprising a bicyclic radical maybe replaced by a —C(O)—, —C(S)—, or —C(═NH)— group. Unless statedotherwise, the valency may be located on any atom of any ring of theheteroaryl group, valency rules permitting. More specifically, the termheteroaryl includes, but is not limited to, 1,2,4-triazolyl,1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl,furanyl, indolyl, 2,3-dihydro-1H-indolyl (including, for example,2,3-dihydro-1H-indo2-yl or 2,3-dihydro-1H-indol-5-yl, and the like),isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl,benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl,phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl,quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl,oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl,isoquinolinyl, tetrahydroisoquinolinyl (including, for example,tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, and the like),pyrrolo[3,2-c]pyridinyl (including, for example,pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, and the like),benzopymnyi, 2,3-dihydrobenzofuranyl, benzo[d][1,3]clioxolyl,2,3-dihydrobenzo[b][1,4]dioxinyl, thiazolyl, isothiazolyl, thiadiazolyl,benzothiazolyl, benzothienyl, and the derivatives thereof, or N-oxide ora protected derivative thereof. The term “5- or 6-membered heteroaryl”describes a subset of the term “heteroaryl.”

“Heteroarylalkyl” means an alkyl group, as defined herein, substitutedwith at least one, specifically one or two heteroaryl group(s), asdefined herein.

“Heterocycloalkyl” means a saturated or partially unsaturated (but notaromatic) monovalent monocyclic group of 3 to 8 ring atoms or asaturated or partially unsaturated (but not aromatic) monovalent fusedor bridged, bicyclic or tricyclic group of 5 to 12 ring atoms in whichone or more, specifically one, two, three, or four ring heteroatomswhere each heteroatom is independently O, S(O)_(n)(n is 0, 1, or 2),—N═, or —NH—, the remaining ring atoms being carbon. One or two ringcarbon atoms may be replaced by a —C(O)—, —C(S)—, or —C(═NH)— group.Unless otherwise stated, the valency of the group may be located on anyatom of any ring within the radical, valency rules permitting. When thepoint of valency is located on a nitrogen atom, R^(y) is absent. Morespecifically the term heterocycloalkyl includes, but is not limited to,azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolyl,piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl,tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl,perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl,isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl,isothiazolidinyl, octahydrocyclopenta[c]pyrrolyl, octahydroindolyl,octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl,tetrahydropyranyl, (3aR,6aS)-5-methyloctahydrocyclopenta[c]pyrrolyl, and(3aS,6aR)-5-methyl-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrolyl, and thederivatives thereof and N-oxide or a protected derivative thereof.

“Heterocycloalkylalkyr means an alkyl radical, as defined herein,substituted with one or two heterocycloalkyl groups, as defined herein,e.g., morpholinylmethyl, N-pyrrolidinylethyl, and3-(N-azetidinyl)propyl, and the like.

“Heterocycloalkyloxy” means an —OR group where R is heterocycloalkyl, asdefined herein.

“Hydroxyalkyl” means an alkyl group, as defined herein, substitued withat least one, prefereably 1, 2, 3, or 4, hydroxy groups.

“Phenylalkyl” means an alkyl group, as defiend herein, substituted withone or two phenyl groups.

“Phenylalkyloxy” means an —OR group where R is phenylalkyl, as definedherein.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. One of ordinary skill in the art would understand that withrespect to any molecule described as containing one or more optionalsubstituents, only sterically practical and/or synthetically feasiblecompounds are meant to be included. “Optionally substituted” refers toall subsequent modifiers in a term, unless stated otherwise. A list ofexemplary optional substitutions is presented below in the definition of“substituted.”

“Optionally substituted aryl” means an aryl group, as defined herein,optionally substituted with one, two, or three substituentsindependently acyl, acylamino, acyloxy, alkyl, haloalkyl, alkenyl,alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl,amino, alkylamino, dialkylamino, nitro, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio,alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonylamino, or aminoalkoxy; or aryl ispentafluorophenyl. Within the optional substituents on “aryl”, the alkyland alkenyl, either alone or as part of another group (including, forexample, the alkyl in alkoxycarbonyl), are independently optionallysubstituted with one, two, three, four, or five halo.

“Optionally substituted arylalkyl” means an alkyl group, as definedherein, substituted with optionally substituted aryl, as defined herein.

“Optionally substituted cycloalkyl” means a cycloalkyl group, as definedherein, substituted with one, two, or three groups independently acyl,acyloxy, acylamino, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy,alkoxycarbonyl, alkenyloxycarbonyl, alkylthio, alkylsulfinyl,alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, halo, hydroxy, amino, alkylamino, dialkylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, nitro,alkoxyalkyloxy, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy,carboxy, or cyano. Within the above optional substitutents on“cycloalkyl”, the alkyl and alkenyl either alone or as part of anothersubstituent on the cycloalkyl ring, are independently optionallysubstituted with one, two, three, four, or five halo, e.g. haloalkyl,haloalkoxy, haloalkenyIoxy, or haloalkylsulfonyl.

“Optionally substituted cycloalkylalkyl” means an alkyl groupsubstituted with at least one, specifically one or two, optionallysubstituted cycloalkyl groups, as defined herein.

“Optionally substituted heteroaryl” means a heteroaryl group optionallysubstituted with one, two, or three substituents independently acyl,acylamino, acyloxy, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, halo,hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino,dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl,alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, aminoalkoxy, alkylaminoalkoxy, ordialkylaminoalkoxy. Within the optional substituents on “heteroaryl”,the alkyl and alkenyl, either alone or as part of another group(including, for example, the alkyl in alkoxycarbonyl), are independentlyoptionally substituted with one, two, three, four, or five halo.

“Optionally substituted heteroarylalkyl” means an alkyl group, asdefined herein, substituted with at least one, specifically one or two,optionally substituted heteroaryl group(s), as defined herein.

“Optionally substituted heterocycloalkyl” means a heterocycloalkylgroup, as defined herein, optionally substituted with one, two, or threesubstituents independently acyl, acylamino, acyloxy, haloalkyl, alkyl,alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl,alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano,alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino,aminoalkoxy, or phenylalkyl. Within the optional substituents on“heterocycloalkyl”, the alkyl and alkenyl, either alone or as part ofanother group (including, for example, the alkyl in alkoxycarbonyl), areindependently optionally substituted with one, two, three, four, or fivehalo.

“Optionally substituted heterocycloalkylalkyl” means an alkyl group, asdefined herein, substituted with at least one, specifically one or two,optionally substituted heterocycloalkyl group(s) as defined herein.

“Optionally substituted phenyl” means a phenyl group optionallysubstituted with one, two, or three substituents independently acyl,acylamino, acyloxy, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, halo,hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino,dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl,alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, or aminoalkoxy, or aryl is pentafluorophenyl. Withinthe optional substituents on “phenyl”, the alkyl and alkenyl, eitheralone or as part of another group (including, for example, the alkyl inalkoxycarbonyl), are independently optionally substituted with one, two,three, four, or five halo.

“Optionally substituted phenylalkyl” means an alkyl group, as definedherein, substituted with one or two optionally substituted phenylgroups, as defined herein.

“Optionally substituted phenylsulfonyl” means an —S(O)₂R group where Ris optionally substituted phenyl, as defined herein.

“Oxo” means an oxygen which is attached via a double bond.

“Yield” for each of the reactions described herein is expressed as apercentage of the theoretical yield.

“Patient” for the purposes of the present invention includes humans andother animals, particularly mammals, and other organisms. Thus themethods are applicable to both human therapy and veterinaryapplications. In a specific embodiment the patient is a mammal, and in amore specific embodiment the patient is human.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. It is understood thatthe pharmaceutically acceptable salts are non-toxic. Additionalinformation on suitable pharmaceutically acceptable salts can be foundin Remington's Pharmaceutical Sciences, 17^(th) ed., Mack PublishingCompany, Easton, Pa., 1985, which is incorporated herein by reference orS. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977;66:1-19 both of which are incorporated herein by reference.

Examples of pharmaceutically acceptable acid addition salts includethose formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like; as wellas organic acids such as acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonicacid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylicacid and the like.

Examples of a pharmaceutically acceptable base addition salts includethose formed when an acidic proton present in the parent compound isreplaced by a metal ion, such as sodium, potassium, lithium. ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Specific salts are the ammonium, potassium, sodium, calcium,and magnesium salts. Salts derived from pharmaceutically acceptableorganic non-toxic bases include, but are not limited to, salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins. Examples of organic bases include isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins,and the like. Exemplary organic bases are isopropylamine, diethylamine,ethanolamine, trimethylamine, dicyclohexylamine, choline, andcaffeine.“Platin(s),” and “platin-containing agent(s)” include, forexample, cisplatin, carboplatin, and oxaliplatin.

“Therapeutically effective amount” is an amount of a compound of theinvention, that when administered to a patient, ameliorates a symptom ofthe disease. The amount of a compound of the invention which constitutesa “therapeutically effective amount” will vary depending on thecompound, the disease state and its severity, the age of the patient tobe treated, and the like. The therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art having regardto their knowledge and to this disclosure.

“Preventing” or “prevention” of a disease, disorder, or syndromeincludes inhibiting the disease from occurring in a human, i.e. causingthe clinical symptoms of the disease, disorder, or syndrome not todevelop in an animal that may be exposed to or predisposed to thedisease, disorder, or syndrome but does not yet experience or displaysymptoms of the disease, disorder, or syndrome.

“Treating” or “treatment” of a disease, disorder, or syndrome, as usedherein, includes (i) inhibiting the disease, disorder, or syndrome,i.e., arresting its development; and (ii) relieving the disease,disorder, or syndrome, i.e., causing regression of the disease,disorder, or syndrome. As is known in the art, adjustments for systemicversus localized delivery, age, body weight, general health, sex, diet,time of administration, drug interaction and the severity of thecondition may be necessary, and will be ascertainable with routineexperimentation by one of ordinary skill in the art.

Embodiments of the Invention

The following paragraphs present a number of embodiments of compounds ofthe invention. In each instance the embodiment includes both the recitedcompounds, as well as a single stereoisomer or mixture of stereoisomersthereof, as well as a pharmaceutically acceptable salt thereof.

Thus, as provided above, in one aspect, the invention provides acompound of Formula I.

In one embodiment, the compound of Formula I is a compound of FormulaI-a or I-b.

In another embodiment, the compound of Formula I is a compound ofFormula I-c.

In another embodiment, the compound of Formula I is a compound ofFormula I-d.

In another embodiment, the compound of Formula I is a compound of I-e.

In another embodiment, in the compound of Formula I, I-a, I-b, I-c, I-d,or I-e, R⁴ is H or methyl.

In another embodiment, in the compound of Formula I, I-a, I-b, I-c, I-d,or I-e, Q is absent or is (C₁-C₄)alkylene and Z is absent or is NH,N(C₁-C6)alkyl, —NH—(C═O)—, —N(C₁-C₆)alkyl-(C═O)—, O, or S.

In another embodiment, the compound of Formula I is a compound ofFormula I-f or I-g, wherein R⁹ is H or CH₃.

In another embodiment, in the compound of Formula I-g, Y is optionallysubstituted (C₁-C₆)alkylene, wherein up to two carbon atoms of the(C₁-C₆)alkylene are replaced by NH, N(C₁-C₆)alkyl, —NH—(C═O)—,—N(C₁-C₆)alkyl-(C═O)—, or —(C═O)—.

In another embodiment, in the compound of Formula I-f or I-g, Q is CH₂or CH(CH₃).

In another embodiment, in the compound of Formula I-f or I-g, Z isabsent or is NH—, —NH—(C O)—, or S.

In another embodiment, in the compound of Formula I-f or I-g, R¹ ishalo, —OH, —NH₂, or cyano, or is (C₁-C₆)alkyl, (C₁-C₆)alkoxy,pyrrolidinyl, piperidinyl, piperizinyl, octahydro-pyridopyrazinyl,pyrazolyl, triazolyl, tetrazolyl, phenyl, pyridyl, imidazolyl,diazepinyi, morpholinyl, —SO₂—(C₁-C₆)alkyl, —SO₂-aryl, —NH—(C₁-C₆)alkyl,—NH—((C₁-C₆)alkyl)₂, octahydroisoquinolinyl, dihydroisoquinolinyl,benzimidazolyl, furanyl, pyrazinyl, thiazolyl,diazabicyclo[2.2.1]hept-2-yl, pyranyl, tetrahydropyranyl, any of whichmay be optionally substituted.

In another embodiment, in the compound of Formula I, I-a, I-b, I-c, I-d,I-e, I-f or I-g, R¹ is bromo, —OH, —NH₂, cyano, —CH₃, —OCH₃, SO₂—CH₃,

In another embodiment, in the compound of Formula I, I-a, I-b, I-c, I-d,I-e, I-f or I-g, R² is NH₂, purinyl, pyrazinyl, pyrazolopyrimidinyl,benzodioxinyl, phenyl, morpholinyl, oxadiazolyl, cyclopropyl, orpyridinyl, any of which may be optionally substituted.

In another embodiment, in the compound of Formula I, I-a, I-b, I-c, I-d,I-e, I-f or I-g, R² is NH₂,

In another aspect, the provides a compound of Formula I which is acompound of Formula II.

In another aspect, the provides a compound of Formula I which is acompound of Formula II-A or II-B, wherein Ra is hydrogen or C₁-C₆-alkyl.

In one embodiment, the compound of Formula II is a compound of FormulaII-A1, II-B1, II-A2, or II-B2.

In another embodiment, in the compound of Formula II, II-A, IL B, A1,II-B1, II-A2, or II-B2, Z is absent or is O, S, —NH— or —NH(C═O)— and R¹and R² are as defined above.

Representative Compounds

Representative compounds of Formula I are depicted below. The examplesare merely illustrative and do not limit the scope of the invention inany way. Compounds of the invention are named according to systematicapplication of the nomenclature rules agreed upon by the InternationalUnion of Pure and Applied Chemistry (IUPAC), International Union ofBiochemistry and Molecular Biology (IUBMB), and the Chemical AbstractsService (CAS). Specifically, names in Table 1 were generated usingACD/Labs naming software 8.00 release, product version 8.08 or higher.

TABLE 1 Compound Structure Name  1

N,8-dimethyl-N-[(1-methylpiperidin- 4-yl)methyl]-3-[(9H-purin-6-ylthio)methyl]quinolin-2-amine  2

3-[(6-amino-9H-purin-9-yl)methyl]- N,8-dimethyl-N-[(1-methylpyrrolidin-2-yl)methyl]quinolin-2-amine  3

3-[(6-amino-9H-purin-9-yl)methyl]- N,8-dimethyl-N-[(1-methylpiperidin-2-yl)methyl]quinolin-2-amine  4

3-[(6-amino-9H-purin-9-yl)methyl]- N,8-dimethyl-N-[(1-methylpiperidin-4-yl)methyl]quinolin-2-amine  5

N-{[2-(2-chlorophenyl)-8- methylquinolin-3-yl]methyl}-2,3-dihydro-1,4-benzodioxin-5-amine  6

1-[2-(2-chlorophenyl)-8- methylquinolin-3-yl]-N-{[3-(methyloxy)phenyl]methyl} methanamine  7

3-({[2-chloro-4- (methyloxy)phenyl]oxy}methyl)-2-(2-chlorophenyl)-8-methylquinoline  8

3-[(1,3-benzodioxol-5-yloxy)methyl]-2-(2-chlorophenyl)-8-methylquinoline  9

N-{[2-(2-chlorophenyl)-8- methylquinolin-3-yl]methyl}-3,5-bis(methyloxy)aniline  10

N-{[2-(2-chlorophenyl)-8- methylquinolin-3-yl]methyl}-3,4-bis(methyloxy)aniline  11

N-{[2-(2-chlorophenyl)-8- methylquinolin-3-yl]methyl}-2-(methyloxy)aniline  12

N-{[8-methyl-2-(octahydro-2H- pyrido(1,2-a]pyrazin-2-yl)quinolin-3-yl]methyl}-9H-purin-6-amine  13

9-{[8-methyl-2-(octahydroisoquinolin- 2(1H)-yl)quinolin-3-yl]methyl}-9H-purin-6-amine  14

9-{[2-(3,4-dihydroisoquinolin-2(1H)- yl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine  15

3-({[3,5- bis(methyloxy)phenyl]oxy}methyl)-2-(2-chlorophenyl)-8-methylquinoline  16

2-(2-chlorophenyl)-8-methyl-3-({[4- (methyloxy)phenyl]oxy}methyl)quinoline  17

2-(2-chlorophenyl)-8-methyl-3-(1- {[4-(methyloxy)phenyl]oxy}ethyl)quinoline  18

N-([2-(2-chlorophenyl)-8- methylquinolin-3-yl]methyl}-3-(methyloxy)aniline  19

N-{[2-(3,4-dihydroisoquinolin-2(1H)- yl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine  20

N,N′-dimethyl-N-[8-methyl-3-({[4- (methyloxy)phenyl]amino}methyl)quinolin-2-yl]ethane-1,2-diamine  21

N,N′-dimethyl-N-[8-methyl-3- (morpholin-4-ylmethyl)quinolin-2-yl]ethane-1,2-diamine  22

N,N′-dimethyl-N-[8-methyl-3-({[3- (methyloxy)phenyl]oxy}methyl)quinolin-2-yl]ethane-1,2-diamine  23

N,N′-dimethyl-N-[8-methyl-3-({[4- (methyloxy)phenyl]oxy}methyl)quinolin-2-yl]ethane-1,2-diamine  24

N,N′-dimethyl-N-[8-methyl-3-({[3- (methyloxy)phenyl]amino}methyl)quinolin-2-yl]ethane-1,2-diamine  25

N,8-dimethyl-N-[2-(methyloxy)ethyl]- 3-[(9H-purin-6-ylamino)methyl]quinoin-2-amine  26

N-butyl-N,8-dimethyl-3-[(9H-purin-6- ylamino)methyl]quinolin-2-amine  27

N-[(8-methyl-2-piperidin-1-ylquinolin- 3-yl)methyl]-9H-purin-6-amine  28

N-{2-[{3-[(6-amino-9H-purin-9- yl)methyl]-8-methylquinolin-2-yl}(methyl)amino]ethyl}-N-methyl-2- (1H-pyrazol-1-yl)acetamide  29

N-{3-[5-(3-aminopyrazin-2-yl)-1,3,4- oxadiazol-2-yl]-8-methylquinolin-2-yl}-N,N′-dimethylethane-1,2-diamine  30

3-amino-N-[(8-methyl-2-{methyl[(1- methylpiperidin-3-yl)methyl]amino}quinolin-3- yl)methyl]pyrazine-2-carboxamide  31

3-amino-N-[(8-methyl-2-{methyl[(1- methylpiperidin-4-yl)methyl]amino}quinolin-3- yl)methyl]pyrazine-2-carboxamide  32

N,8-dimethyl-N-[(1-methylpiperidin- 3-yl)methyl]-3-[(9H-purin-6-ylamino)methyl]quinolin-2-amine  33

N,8-dimethyl-N-[(1-methylpiperidin- 4-yl)methyl]-3-[(9H-purin-6-ylamino)methyl]quinolin-2-amine  34

N-{2-[{3-[(6-amino-9H-purin-9- yl)methyl]-8-methylquinolin-2-yl}(methyl)amino]ethyl}-N-methyl-2 (1H-1,2,3-triazol-1-yl)acetamide  35

N-methyl-N-[2-(methyl{8-methyl-3- [(9H-purin-6-ylamino)methyl]quinolin-2- yl}amino)ethyl]-2-(1H-1,2,3-triazol-1-yl)acetamide  36

N,N′-dimethyl-N-{8-methyl-3-[(9H- purin-6-ylamino)methyl]quinolin-2-yl}ethane-1,2-diamine  37

N-[(8-methyl-2-piperazin-1- ylquinolin-3-yl)methyl]-9H-purin-6- amine 38

N,8-dimethyl-N-[(1-methylpipendin- 2-yl)methyl]-3-[(9H-purin-6-ylamino)methyl]quinolin-2-amine  39

3-amino-N-[(8-methyl-2-{methyl[(1- methylpiperidin-2-yl)methyl]amino}quinolin-3- yl)methyl]pyrazine-2-carboxamide  40

N-methyl-N′-[(8-methyl-2-{methyl[2- (methylamino)ethyl]amino}quinolin-3-yl)methyl]cyclopropane-1,1- dicarboxamide  41

3-{[3-(4-acetylpiperazin-1- yl)quinoxalin-2-yl]amino}benzamide  42

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(1H-tetrazol-1-ylacetyl)amino]ethyl}amino)quinolin- 3-yl]methyl}pyrazine-2-carboxamide 43

3-amino-N-({2-[(2-{[(3,5-dimethyl- 1H-1,2,4-triazol-1-yl)acetyl](methyl)amino}ethyl)(methyl) amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide  44

3-amino-N-{[2-(3-{[2- (dimethylamino)-2oxoethyl]amino}pyrrolidin-1-yl)-8- methylquinolin-3-yl]methyl}pyrazine-2-carboxamide  45

3-amino-N-[(8-methyl-2-{3-[(1H- 1,2,3-triazol-1-ylacetyl)amino]pyrrolidin-1- yl}quinolin-3-yl)methyl]pyrazine-2-carboxamide  46

3-amino-N-({2-[bis(pyridin-3- ylmethyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide  47

3-amino-N-({2-[bis(pyridin-2- ylmethyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide  48

3-amino-N-[(5-chloro-3-{2- [(dimethylamino)methyl]phenyl}quinolin-2-yl)methyl]pyrazine-2- carboxamide  49

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(1H-pyrazol-1-ylacetyl)amino]ethyl}amino)quinolin- 3-yl]methyl}pyrazine-2-carboxamide 50

3-amino-N-{[2-(3-hydroxypropyl)-8- methylquinolin-3-yl]methyl}pyrazine-2-carboxamide  51

3-amino-N-{[8-methyl-2-(methyl{2- [(1H-1,2,3-triazol-1-ylacetyl)amino]ethyl}amino)quinolin- 3-yl]methyl}pyrazine-2-carboxamide 52

3-amino-N-[(3-{2- [(dimethylamino)methyl]phenyl}-5-methylquinolin-2-yl)methyl]pyrazine- 2-carboxamide  53

3-amino-N-({2-[4-(1H-benzimidazol- 1-ylacetyl)-1,4-diazepan-1-yl]-8-methylquinolin-3-yl}methyl)pyrazine- 2-carboxamide  54

3-amino-N-({2-[4-(1H-imidazol-1- ylacetyl)-1,4-diazepan-1-yl]-8-methylquinolin-3-yl}methyl)pyrazine- 2-carboxamide  55

3-amino-N-[(8-methyl-2-{4-[(2- methyl-1H-imidazol-1-yl)acetyl]-1,4-diazepan-1-yl}quinolin-3- yl)methyl]pyrazine-2-carboxamide  56

3-amino-N-[(3-{2- [(dimethylamino)carbonyl]phenyl}quinolin-2-yl)methyl]pyrazine-2- carboxamide  57

3-amino-N-[(8-methyl-2-{4-[(1- methyl-1H-pyrrol-2-yl)methyl]-1,4-diazepan-1-yl}quinolin-3- yl)methyl]pyrazine-2-carboxamide  58

3-amino-N-[(8-methyl-2-{4-[(5- methylfuran-2-yl)methyl]-1,4-diazepan-1-yl}quinolin-3- yl)methyl]pyrazine-2-carboxamide  59

3-amino-N-({3-[2-(piperidin-1- ylmethyl)phenyl]quinolin-2-yl}methyl)pyrazine-2-carboxamide  60

3-amino-N-({8-methyl-2-[4-(1H-1,2,3- triazol-1-ylacetyl)-1,4-diazepan-1-yl]quinolin-3-yl}methyl)pyrazine-2- carboxamide  61

3-amino-N-({8-methyl-2-[4-(2H-1,2,3- triazol-2-ylacetyl)-1,4-diazepan-1-yl]quinolin-3-yl}methyl)pyrazine-2- carboxamide  62

3-amino-N-[(8-methyl-2-{4-[(1- methyl-1H-imidazol-2-yl)methyl]-1,4-diazepan-1-yl}quinolin-3- yl)methyl]pyrazine-2-carboxamide  63

3-amino-N-[(8-methyl-2-{4-[(1- methyl-1H-imidazol-5-yl)methyl]-1,4-diazepan-1-yl}quinolin-3- yl)methyl]pyrazine-2-carboxamide  64

3-amino-N-({8-methyl-2-[4-(pyridin- 3-ylmethyl)-1,4-diazepan-1-yl]quinolin-3-yl}methyl)pyrazine-2- carboxamide  65

3-amino-N-({8-methyl-2-[4-(pyridin- 4-ylmethyl)-1,4-diazepan-1-yl]quinolin-3-yl}methyl)pyrazine-2- carboxamide  66

3-amino-N-[(2-{4-[2- (dimethylamino)-2-oxoethyl]-1,4-diazepan-1-yl}-8-methylquinolin-3- yl)methyl]pyrazine-2-carboxamide  67

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(1-propyl-D-prolyl)amino]ethyl}amino)quinolin-3- yl]methyl}pyrazine-2-carboxamide 68

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(pyridin-2-ylmethyl)amino]ethyl}amino)quinolin- 3-yl]methyl}pyrazine-2-carboxamide 69

3-amino-N-[(3-{3- [(dimethylamino)methyl]phenyl}quinolin-2-yl)methyl]pyrazine-2- carboxamide  70

3-amino-N-({3-[2-(morpholin-4- ylmethyl)phenyl]quinolin-2-yl}methyl)pyrazine-2-carboxamide  71

3-amino-N-({3-[4-(morpholin-4- ylmethyl)phenyl]quinolin-2-yl}methyl)pyrazine-2-carboxamide  72

3-amino-N-({3-[3-(morpholin-4- ylmethyl)phenyl]quinolin-2-yl}methyl)pyrazine-2-carboxamide  73

3-amino-N-({8-methyl-2-[methyl(2- {methyl[1-(1-methylethyl)-D-prolyl]amino}ethyl)amino]quinolin-3- yl}methyl)pyrazine-2-carboxamide 74

2-amino-N-{[3-(2- methylphenyl)quinolin-2-yl]methyl}pyrimidine-5-carboxamide  75

3-amino-N-{1-[3-(2- methylphenyl)quinolin-2-yl]ethyl}pyrazine-2-carboxamide  76

3-amino-N-({8-methyl-2-[methyl(2- {methyl[2-(methylamino)-2-oxoethyl]amino}ethyl)amino]quinolin- 3-yl}methyl)pyrazine-2-carboxamide 77

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(2-morpholin-4-yl-2-oxoethyl)amino]ethyl}amino)quinolin- 3-yl]methyl}pyrazine-2-carboxamide 78

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(pyrazin-2-ylcarbonyl)amino]ethyl}amino) quinolin-3-yl]methyl}pyrazine-2-carboxamide  79

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(pyridin-4-ylcarbonyl)amino]ethyl}amino) quinolin-3-yl]methyl}pyrazine-2-carboxamide  80

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(pyridin-3-ylcarbonyl)amino]ethyl}amino) quinolin-3-yl]methyl}pyrazine-2-carboxamide  81

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(pyridin-2-ylcarbonyl)amino]ethyl}amino) quinolin-3-yl]methyl}pyrazine-2-carboxamide  82

3-amino-N-({8-methyl-2-[methyl(2- {methyl[(4-methylphenyl)sulfonyl]amino}ethyl) amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide  83

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(pyridin-3-ylmethyl)amino]ethyl}amino)quinolin- 3-yl]methyl}pyrazine-2-carboxamide 84

3-amino-N-({2-[{2- [(cyanomethyl)(methyl)amino]ethyl}(methyl)amino]-8-methylquinolin-3- yl}methyl)pyrazine-2-carboxamide  85

3-amino-N-({2-[{2-[(1H-imidazol-1- ylacetyl)(methyl)amino]ethyl}(methyl)amino]-8-methylquinolin-3- yl}methyl)pyrazine-2-carboxamide  86

3-amino-N-({8-methyl-2-[methyl(2- {methyl[(2-methyl-1H-imidazol-1-yl)acetyl]amino}ethyl)amino]quinolin- 3-yl}methyl)pyrazine-2-carboxamide 87

3-amino-N-({8-methyl-2- [methyl(pyridin-3- ylmethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide  88

3-amino-N-({8-methyl-2-[methyl(2- pyridin-2-ylethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide  89

3-amino-N-({2-[(2-{[2- (dimethylamino)-2-oxoethyl](methyl)amino}ethyl)(methyl) amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide  90

3-amino-N-([8-methyl-2-(methyl{2- [methyl(pyrazin-2-yl)amino]ethyl}amino)quinolin-3- yl]methyl}pyrazine-2-carboxamide  91

3-amino-N-{[3-{1,3-thiazol-4- yl)quinolin-2-yl]methyl}pyrazine-2-carboxamide  92

3-amino-N-[(3-{2- [(dimethylamino)methyl]phenyl)quinolin-2-yl)methyl]pyrazine-2- carboxamide  93

3-amino-N-[(3-bromoquinolin-2- yl)methyl]pyrazine-2-carboxamide  94

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(2H-1,2,3-triazol-2-ylacetyl)amino]ethyl}amino)quinolin- 3-yl]methyl}pyrazine-2-carboxamide 95

3-amino-N-({8-methyl-2-[(pyridin-3- ylmethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide  96

3-amino-N-({8-methyl-2-[(2-pyridin- 2-ylethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide  97

3-amino-N-({8-methyl-2-[(2-pyridin- 3-ylethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide  98

3-amino-N-({8-methyl-2-[methyl(1- methylpyrrolidin-3-yl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide  99

3-amino-N-({8-methyl-2-[methyl(1- methylpiperidin-4-yl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide 100

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(1H-1,2,3-triazol-1-ylacetyl)amino]ethyl)amino)quinolin- 3-yl]methyl}pyrazine-2-carboxamide101

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(methylsulfonyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine- 2-carboxamide 102

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(D-prolyl)amino]ethyl}amino)quinolin-3- yl]methyl}pyrazine-2-carboxamide103

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(L-prolyl)amino]ethyl}amino)quinolin-3- yl]methyl}pyrazine-2-carboxamide104

3-amino-N-[(8-methyl-2-{methyl[2- (methyloxy)ethyl]amino}quinolin-3-yl)methyl]pyrazine-2-carboxamide 105

3-amino-N-{[3-(2- methylphenyl)quinolin-2-yl]methyl}-5-morpholin-4-ylpyrazine-2- carboxamide 106

3-amino-5-(methyloxy)-N-{[3-(2- methylphenyl)quinolin-2-yl]methyl}pyrazine-2-carboxamide 107

3-amino-5-chloro-N-{[3-(2- methylphenyl)quinolin-2-yl]methyl}pyrazine-2-carboxamide 108

4-amino-N-{[3-(2- methylphenyl)quinolin-2-yl]methyl}pyrimidine-5-carboxamide 109

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(pyrrolidin-1-ylacetyl)amino]ethyl}amino)quinolin- 3-yl]methyl}pyrazine-2-carboxamide110

3-amino-N-({8-methyl-2-[methyl(2- {methyl[(1-methyl-1H-imidazol-5-yl)carbonyl]amino}ethyl)amino] quinolin-3-yl}methyl)pyrazine-2-carboxamide 111

3-amino-N-{[2-(1H-imidazol-1-yl)-8- methylquinolin-3-yl]methyl}pyrazine-2-carboxamide 112

3-amino-N-{[2-(1H-benzimidazol-1- yl)-8-methylquinolin-3-yl]methyl}pyrazine-2-carboxamide 113

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(1-methyl-L-prolyl)amino]ethyl}amino)quinolin-3- yl]methyl}pyrazine-2-carboxamide114

3-amino-N-({2-[{2-[(N,N- dimethylglycyl)(methyl)amino]ethyl}(methyl)amino]-8-methylquinolin-3- yl}methyl)pyrazine-2-carboxamide 115

3-amino-N-({2-[{2- [glycyl(methyl)amino]ethyl}(methyl)amino]-8-methylquinolin-3- yl}methyl)pyrazine-2-carboxamide 116

3-amino-N-{[8-methyl-2-(methyl{2- [methyl(N-methylglycyl)amino]ethyl}amino) quinolin-3-yl]methyl}pyrazine-2-carboxamide 117

3-iodo-1-{1-[3-(2- methylphenyl)quinolin-2-yl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4- amine 118

3-amino-N-{[5-methyl-3-(2- methylphenyl)quinolin-2-yl]methyl}pyrazine-2-carboxamide 119

3-iodo-1-{[5-methyl-3-(2- methylphenyl)quinolin-2-yl]methyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine 120

9-{[3-(2-methylphenyl)naphthalen-2- yl]methyl}-9H-purin-6-amine 121

3-amino-N-({2-[(2- hydroxyethyl)(methyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine- 2-carboxamide 122

3-amino-N-[(8-methyl-2-{[2- (methylamino)ethyl]oxy}quinolin-3-yl)methyl]pyrazine-2-carboxamide 123

3-amino-N-({2-[(2R,5S)-2,5- dimethylpiperazin-1-yl]-8-methylquinolin-3-yl}methyl)pyrazine- 2-carboxamide 124

N-{[2-(4-acetylpiperazin-1-yl)-8- methylquinolin-3-yl]methyl}-3-aminopyrazine-2-carboxamide 125

3-amino-N-({2-[(2- hydroxyethyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine- 2-carboxamide 126

1,1-dimethylethyl {1-[3-({[(3- aminopyrazin-2-yl)carbonyl]amino}methyl)-8- methylquinolin-2-yl]piperidin-4-yl}methylcarbamate 127

3-amino-N-({2-[4- (dimethylamino)piperidin-1-yl]-8-methylquinolin-3-yl}methyl)pyrazine- 2-carboxamide 128

3-amino-N-[(2-{[2- (dimethylamino)ethyl](methyl)amino}-8-methylquinolin-3- yl)methyl]pyrazine-2-carboxamide 129

3-amino-N-[(2-{[2- (dimethylamino)ethyl]amino}-8-methylquinolin-3-yl)methyl]pyrazine- 2-carboxamide 130

3-amino-N-[(8-methyl-2-{methyl[2- (methylamino)ethyl]amino}quinolin-3-yl)methyl]pyrazine-2-carboxamide 131

3-amino-N-[(8-methyl-2-piperazin-1- ylquinolin-3-yl)methyl]pyrazine-2-carboxamide 132

N-5-{[3-(2-methylphenyl)quinolin-2- yl]methyl}pyrimidine-4,5-diamine 133

3-amino-N-[(8-methyl-2-{methyl[3- (methylamino)propyl]amino}quinolin-3-yl)methyl]pyrazine-2-carboxamide 134

3-iodo-1-{[8-methyl-2-(2- methylphenyl)quinolin-3-yl]methyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine 135

3-iodo-N-{[8-methyl-2-(2- methylphenyl)quinolin-3-yl]methyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine 136

3-amino-N-({2-[{3-[(N,N- dimethylglycyl)(methyl)amino]propyl}(methyl)amino]-8-methylquinolin-3- yl}methyl)pyrazine-2-carboxamide 137

3-amino-N-({2-[4-(N,N- dimethylglycyl)-1,4-diazepan-1-yl]-8-methylquinolin-3-yl}methyl)pyrazine- 2-carboxamide 138

3-amino-N-[(2-{[3- (dimethylamino)propyl]amino}-8-methylquinolin-3-yl)methyl]pyrazine- 2-carboxamide 139

3-amino-N-{[2-(1,4-diazepan-1-yl)-8-methylquinolin-3-yl]methyl}pyrazine- 2-carboxamide 140

3-amino-N-{[8-methyl-2-(4-methyl- 1,4-diazepan-1-yl)quinolin-3-yl]methyl}pyrazine-2-carboxamide 141

3-bromo-N-{[3-(2- methylphenyl)quinolin-2-yl]methyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine 142

3-amino-N-{[3-(2- methylphenyl)quinolin-2-yl]methyl)pyrazine-2-carboxamide 143

N-{[2-(4-acetylpiperazin-1-yl)-8- methylquinolin-3-yl]methyl}-9H-purin-6-amine 144

N-{[2-(4-ethylpiperazin-1-yl)-8- methylquinolin-3-yl]methyl}-9H-purin-6-amine 145

3-iodo-1-{[3-(2- methylphenyl)quinolin-2-yl]methyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine 146

N-{[8-methyl-2-(4-methyl-1,4- diazepan-1-yl)quinolin-3-yl]methyl}-9H-purin-6-amine 147

3-amino-N-[(8-methyl-2-piperidin-1- ylquinolin-3-yl)methyl]pyrazine-2-carboxamide 148

3-amino-N-{[2-(2-chlorophenyl)-8- methylquinolin-3-yl]methyl}pyrazine-2-carboxamide 149

N-{3-[(6-amino-9H-purin-9- yl)methyl]-8-methylquinolin-2-yl}-N,N′-dimethylethane-1,2-diamine 150

9-{[8-methyl-2-(5-methyl-2,5- diazabicyclo[2.2.1]hept-2-yl)quinolin-3-yl]methyl}-9H-purin-6-amine 151

N-{[5-methyl-3-(2-methylphenyl)-4- oxo-3,4-dihydroquinazolin-2-yl]methyl}-3-morpholin-4-ylpyrazine- 2-carboxamide 152

N-{1-[2-(2-chloropheny))-8- methylquinolin-3-yl]ethyl}-9H-purin- 6-amine153

N-{3-[(6-amino-9H-purin-9- yl)methyl]-8-methylquinolin-2-yl}methanesulfonamide 154

N-{[2-(2-chlorophenyl)-8- methylquinolin-3-yl]methyl}-9H- purin-6-amine155

N-{[3-(2-methylphenyl)quinolin-2- yl]methyl}-9H-purin-6-amine 156

N-{3-[(6-amino-9H-purin-9- yl)methyl}-8-methylquinolin-2-yl}benzenesulfonamide 157

2-(2-aminoethyl)-5-methyl-3-(2- methylphenyl)quinazolin-4(3H)-one 158

3-({[3,5- bis(methyloxy)phenyl]methyl}oxy)-8-methyl-2-(2-methylphenyl)quinoline 159

3-chloro-N-{[5-methyl-3-(2- methylphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl]methyl}pyrazine-2-carboxamide 160

3-amino-6-bromo-N-{[5-methyl-3-(2- methylphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl]methyl}pyrazine-2-carboxamide 161

3-amino-N-{[5-methyl-3-(2- methylphenyl)-4-oxo-3,4- dihydroquinazolin-2-yl]methyl}pyridine-2-carboxamate 162

2-[(6-amino-9H-purin-9-yl)methyl]-3 (2-methylphenyl)thieno[3,2-d]pyrimidin-4(3H)-one 163

3-(2-methylphenyl)-2-[(7H-purin-6- ylthio)methyl]thieno[3,2-d]pyrimidin4(3H)-one 164

3-[(6-amino-9H-purin-9-yl)methyl]-8- methyl-N-(1-methylpiperidin-4-yl)quinolin-2-amine 165

3-[(6-amino-9H-purin-9-yl)methyl]-8- methyl-N-(tetrahydro-2H-pyran-4-yl)quinolin-2-amine 166

9-{[2-(4-acetylpiperazin-1-yl)-8- methylquinolin-3-yl]methyl}-9H-purin-6-amine 167

3-[(6-amino-9H-purin-9-yl)methyl]-8- methyl-N-[2-(methyloxy)ethyl]quinolin-2-amine 168

9-{[4-methyl-3-(2- methylphenyl)quinolin-2-yl]methyl}- 9H-purin-6-amine169

7-{[4-methyl-3-(2- methylphenyl)quinolin-2-yl]methyl}- 7H-purin-6-amine170

9-{[8-methyl-2-(2-methylpyrrolidin-1-yl)quinolin-3-yl]methyl}-9H-purin-6- amine 171

9-[(8-methyl-2-pyrrolidin-1- ylquinolin-3-yl)methyl]-9H-purin-6- amine172

9-[(8-methyl-2-piperazin-1-ylquinolin- 3-yl)methyl]-9H-purin-6-amine 173

9-{[8-methyl-2-(4-methylpiperazin-1-yl)quinolin-3-yl]methyl}-9H-purin-6- amine 174

2-amino-N-{[5-methyl-3-(2- methylphenyl)-4-oxo-3,4- dihydroquinazolin-2-yl]methyl}pyridine-4-carboxamide 175

3-amino-N-{[5-methyl-3-(2- methylphenyl)-4-oxo-3,4- dihydroquinazolin-2-yl]methyl}pyrazine-2-carboxamide 176

2-amino-N-{[5-methyl-3-(2- methylphenyl)-4-oxo-3,4- dihydroquinazolin-2-yl]methyl}pyridine-3-carboxamide 177

9-[(8-methyl-2-morpholin-4- ylquinolin-3-yl)methyl]-9H-purin-6- amine178

7-{[3-(2-methylphenyl)quinolin-2- yl]methyl}-7H-purin-6-amine 179

9-{[3-(2-methylphenyl)quinolin-2- yl]methyl}-9H-purin-6-amine 180

9-{[2-(2,3-dimethylphenyl)-8- methylquinolin-3-yl]methyl}-9H-purin-6-amine 181

9-{[2-(2,5-dimethylphenyl)-8- methylquinolin-3-yl]methyl}-9H-purin-6-amine 182

9-({8-methyl-2-[2- (trifluoromethyl)phenyl]quinolin-3-yl}methyl)-9H-purin-6-amine 183

9-{[8-methyl-2-(3- methylphenyl)quinolin-3-yl]methyl}- 9H-purin-6-amine184

9-{[8-methyl-2-(3-{[2- (methyloxy)ethyl]oxy}phenyl)quinolin-3-yl]methyl}-9H-purin-6-amine 185

9-({8-methyl-2-[3- (methyloxy)phenyl]quinolin-3-yl}methyl)-9H-purin-6-amine 186

9-({2-[2-(ethyloxy)phenyl]-8- methylquinolin-3-yl}methyl)-9H-purin-6-amine 187

9-{[2-(2-chlorophenyl)-8- methylquinolin-3-yl]methyl}-9H- purin-6-amine188

8-methyl-2-(2-methylphenyl)-3-[(9H- purin-6-ylthio)methyl]quinoline 189

9-{[8-methyl-2-(2- methylphenyl)quinolin-3-yl]methyl}- 9H-purin-6-amine190

9-([3-(2-methylphenyl)quinoxalin-2- yl]methyl}-9H-purin-6-amine 191

9-{[2-(2-methylphenyl)quinolin-3- yl]methyl}-9H-purin-6-amine

In another aspect, the invention provides a pharmaceutical compositionwhich comprises 1) a compound, as a single stereoisomer or mixture ofisomers thereof, according to any one of Formula compounds of Formula I,or according to any one of the above embodiments or a compound in Table1, optionally as a pharmaceutically acceptable salt thereof, and 2) apharmaceutically acceptable carrier, excipient, and/or diluent thereof.

In another aspect, the invention provides a method of treating disease,disorder, or syndrome where the disease is associated with uncontrolled,abnormal, and/or unwanted cellular activities effected directly orindirectly by PI3K delta which method comprises administering to a humanin need thereof a therapeutically effective amount of a compound of anyof Formula to any one of Formula compounds of Formula I, a compound ofany one of the above embodiments, or a compound from Table 1, optionallyas a pharmaceutically acceptable salt or pharmaceutical compositionthereof. In another embodiment of embodiment (V), the disease is cancer.In another embodiment of embodiment (V), the disease is cancer and theCompound is of Formula I or a Compound from Table 1.

In another aspect, the invention provides a method of treating adisease, disorder, or syndrome which method comprises administering to apatient a therapeutically effective amount of a compound of any ofFormula I, a compound of any one of the above embodiments, or a compoundfrom Table 1, optionally as a pharmaceutically acceptable salt thereof,or a pharmaceutical composition comprising a therapeutically effectiveamount of a compound of Formula I, a compound of any one of the aboveembodiments, or a compound from Table 1, and a pharmaceuticallyacceptable carrier, excipient, or diluent.

In another embodiment, the disease is cancer. and the Compound is thecompound of Formula I or a compound from Table 1.

General Administration

In one aspect, the invention provides pharmaceutical compositionscomprising an inhibitor of PI3K delta according to the invention and apharmaceutically acceptable carrier, excipient, or diluent. In certainother specific embodiments, administration is by the oral route.Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally(intravenous, intramuscular, or subcutaneous), topically, transdermally,intravaginally, intravesically, intracistemally, or rectally, in theform of solid, semi-solid, lyophilized powder, or liquid dosage forms,such as for example, tablets, suppositories, pills, soft elastic andhard gelatin capsules, powders, solutions, suspensions, or aerosols, orthe like, specifically in unit dosage forms suitable for simpleadministration of precise dosages.

The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include carriers and adjuvants, etc.

Adjuvants include preserving, wetting, suspending, sweetening,flavoring, perfuming, emulsifying, and dispensing agents. Prevention ofthe action of microorganisms can be ensured by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, and the like. It may also be desirable to include isotonic agents,for example sugars, sodium chloride, and the like. Prolonged absorptionof the injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

If desired, a pharmaceutical composition of the invention may alsocontain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylalted hydroxytoluene, etc.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules) and the bioavailability of the drugsubstance. Recently, pharmaceutical formulations have been developedespecially for drugs that show poor bioavailability based upon theprinciple that bioavailability can be increased by increasing thesurface area i.e., decreasing particle size. For example, U.S. Pat. No.4,107,288 describes a pharmaceutical formulation having particles in thesize range from 10 to 1,000 nm in which the active material is supportedon a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684describes the production of a pharmaceutical formulation in which thedrug substance is pulverized to nanoparticles (average particle size of400 nm) in the presence of a surface modifier and then dispersed in aliquid medium to give a pharmaceutical formulation that exhibitsremarkably high bioavailability.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

One specific route of administration is oral, using a convenient dailydosage regimen that can be adjusted according to the degree of severityof the disease-state to be treated.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid, (b) binders, as for example, cellulosederivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose,and gum acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, croscarmellose sodium, complexsilicates, and sodium carbonate, (e) solution retarders, as for exampleparaffin, (t) absorption accelerators, as for example, quaternaryammonium compounds, (g) wetting agents, as for example, cetyl alcohol,and glycerol monostearate, magnesium stearate and the like (h)adsorbents, as for example, kaolin and bentonite, and (i) lubricants, asfor example, talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In thecase of capsules, tablets, and pills, the dosage forms may also comprisebuffering agents.

Solid dosage forms as described above can be prepared with coatings andshells, such as enteric coatings and others well known in the art. Theymay contain pacifying agents, and can also be of such composition thatthey release the active compound or compounds in a certain part of theintestinal tract in a delayed manner. Examples of embedded compositionsthat can be used are polymeric substances and waxes. The activecompounds can also be in microencapsulated form, if appropriate, withone or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Suchdosage forms are prepared, for example, by dissolving, dispersing, etc.,a compound(s) of the invention, or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike; solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide; oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan; or mixtures of these substances, and the like, to thereby forma solution or suspension.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are, for example, suppositoriesthat can be prepared by mixing the compounds of the present inventionwith for example suitable non-irritating excipients or carriers such ascocoa butter, polyethyleneglycol or a suppository wax, which are solidat ordinary temperatures but liquid at body temperature and therefore,melt while in a suitable body cavity and release the active componenttherein.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. In one example, the composition will bebetween about 5% and about 75% by weight of a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, with the restbeing suitable pharmaceutical excipients.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state in accordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptablesalts or solvates, are administered in a therapeutically effectiveamount which will vary depending upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of the compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular disease-states, and the hostundergoing therapy. The compounds of the present invention can beadministered to a patient at dosage levels in the range of about 0.1 toabout 1,000 mg per day. For a normal human adult having a body weight ofabout 70 kilograms, a dosage in the range of about 0.01 to about 100 mgper kilogram of body weight per day is an example. The specific dosageused, however, can vary. For example, the dosage can depend on a numberof factors including the requirements of the patient, the severity ofthe condition being treated, and the pharmacological activity of thecompound being used. The determination of optimum dosages for aparticular patient is well known to one of ordinary skill in the art.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described above andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention may alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

Utility

Compounds of the Invention have activity for PI3K-delta. Compounds ofthis invention have been tested using the assays described in theBiological Examples and have been determined to be inhibitors ofPI3K-delta. Suitable in vitro assays for measuring PI3K delta activityand the inhibition thereof by compounds are known in the art. Forfurther details of an in vitro assay for measuring P13K delta, see theBiological Examples herein. Cell-based assays for measurement of invitro efficacy in treatment of cancer are known in the art. In addition,assays are described in the Biological Examples provided herein.Suitable in vivo models for cancer are known to those of ordinary skillin the art. For further details of in vivo models for prostateadenocarcinoma, glioblastoma, lung carcinoma, and melanoma, see theBiological Examples described herein. Following the examples disclosedherein, as well as that disclosed in the art, a person of ordinary skillin the art can determine the activity of a compound of this invention.

Compounds of Formula I are useful for treating diseases, includingautoimmune disorders, inflammatory diseases, and cancers, which arelisted below.

Cancers: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung:bronchogenic carcinoma (squamous cell, undifferentiated small cell,undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar)carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoushanlartoma, mesothelioma; Gastrointestinal: esophagus (squamous cellcarcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach(carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma,insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), smallbowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma [pinealoma], glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus(endometrial carcinoma), cervix (cervical carcinoma, pm-tumor cervicaldysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecalcell tumors, SertoliLeydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma],fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acuteand chronic], acute lymphoblastic leukemia, chronic lymphocyticleukemia, myeloproliferative diseases, multiple myeloma, myelodysplasticsyndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignantlymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cellcarcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

Autoimmune diseases: Hashimoto's thyroiditis, systemic lupuserythematosus (SLE), Goodpasture's syndrome, pemphigus, receptorautoimmune diseases, Basedow's disease (Graves' disease), myastherniagravis, insulin resistant diseases, autoimmune hemolytic anemia,autoimmune thrombocytopenic purpura, autoimmune encephalomyelitis,rheumatism, rheumatoid arthritis, scleroderma, mixed connective tissuedisease, polymyositis, pernicious anemia, idiopathic Addison's disease,some types of infertility, glomerulonephritis, bullous pemphigus,Sjogren's syndrome, some types of diabetes, adrenergic agent resistance,chronic active hepatitis, primary binary cirrhosis, endocrine failure,vitiligo, angiitis, post-cardiac surgery syndrome, urticaria, atopicdermatiti and multiple sclerosis, autoimmune polyglandular disease (alsoknown as autoimmune polyglandular syndrome), autoimmune alopecia;pernicious anemia; vitiligo; autoimmune hypopituatarism, andGuillain-Barre syndrome.

Inflammatory Diseases: asthma, allergic rhinitis, psoriasis,inflammatory arthritis, rheumatoid arthritis, psoriatic arthritis orosteoarthritis, irritable bowel syndrome, ulcerative colitis, Crohn'sdisease, respiratory allergies (asthma, hay fever, allergic rhinitis) orskin allergies, scleracierma, mycosis fungoides, acute inflammatoryresponses (such as acute respiratory distress syndrome andishchemia/reperfusion injury), dermatomyositis, alopecia greats, chronicactinic dermatitis, eczema, Behcet's disease, Pustulosis palmoplanteris,Pyoderma gangrenum, Sezary's syndrome, atopic dermatitis, systemicsclerosis, and morphea.

Thus, in one embodiment, the invention provides a method of inhibitingPI3K delta comprising contacting the PI3K delta with an effective amountof a compound as disclosed herein.

In another embodiment, the inventnion provides a method of treating aPI3K delta modulated disease comprising administering to a mammal inneed of such treatment a therapeutically effective amount of a compoundas disclosed herein.

In another embodiment, the invention provides a method of treatingcancer disease mediated by PI3K delta comprising administering to amammal in need of such treatment a therapeutically effective amount of acompound of claims 1-20.

Compounds of the invention are also useful as inhibitors of PI3Kdeita invivo for studying the in vivo role of PI3K delta in biologicalprocesses, including the diseases described herein. Accordingly, theinvention also comprises a method of inhibiting PI3K delta in vivocomprising administering a compound or composition of the invention to amammal.

General Synthesis

Compounds of this invention can be made by the synthetic proceduresdescribed below. The starting materials and reagents used in preparingthese compounds are either available from commercial suppliers such asAldrich Chemical Co. (Milwaukee, Wis.), or Bachem (Torrance, Calif.), orare prepared by methods known to those skilled in the art followingprocedures set forth in references such as Fieser and Fieser's Reagentsfor Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd'sChemistry of Carbon Compounds, Volumes 1-5 and Supplementals (ElsevierScience Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wileyand Sons, 1991), March's Advanced Organic Chemistry, (John Wiley andSons, 4^(th) Edition) and Larock's Comprehensive Organic Transformations(VCH Publishers Inc., 1989). These schemes are merely illustrative ofsome methods by which the compounds of this invention can besynthesized, and various modifications to these schemes can be made andwill be suggested to one skilled in the art having referred to thisdisclosure. The starting materials and the intermediates of the reactionmay be isolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure and over a temperature range from about−78° C. to about 150° C., more specifically from about 0° C. to about125° C. and more specifically at about room (or ambient) temperature,e.g., about 20° C. Unless otherwise stated (as in the case ofhydrogenation), all reactions are performed under an atmosphere ofnitrogen.

Prodrugs can be prepared by techniques known to one skilled in the art.These techniques generally modify appropriate functional groups in agiven compound. These modified functional groups regenerate originalfunctional groups by routine manipulation or in vivo. Amides and estersof the compounds of the present invention may be prepared according toconventional methods. A thorough discussion of prodrugs is provided inT. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms or quaternized nitrogen atoms intheir structure. Compounds of the Invention that may be prepared throughthe syntheses described herein may exist as single stereoisomers,racemates, and as mixtures of enantiomers and diastereomers. Thecompounds may also exist as geometric isomers. All such singlestereoisomers, racemates and mixtures thereof, and geometric isomers areintended to be within the scope of this invention.

Some of the compounds of the invention contain an active ketone —C(O)CF₃and may exist in part or in whole as the —C(OH₂)CF₃ form. Regardless ofwhether the compound is drawn as the —C(O)CF₃ or —C(OH₂)CF₃ form, bothare included within the scope of the Invention. Although an individualcompound may be drawn as the —C(O)CF₃ form, one of ordinary skill in theart would understand that the compound may exist in part or in whole asthe —C(OH₂)CF₃ form and that the ratio of the two forms may varydepending on the compound and the conditions in which it exists.

Some of the compounds of the invention may exist as tautomers. Forexample, where a ketone or aldehyde is present, the molecule may existin the enol form; where an amide is present, the molecule may exist asthe imidic acid; and where an enamine is present, the molecule may existas an imine. Ali such tautomers are within the scope of the invention.Regardless of which structure or which terminology is used, eachtautomer is included within the scope of the Invention. The presentinvention also includes N-oxide derivatives and protected derivatives ofcompounds of the Invention. For example, when compounds of the Inventioncontain an oxidizable nitrogen atom, the nitrogen atom can be convertedto an N-oxide by methods well known in the art. When compounds of theInvention contain groups such as hydroxy, carboxy, thiol or any groupcontaining a nitrogen atom(s), these groups can be protected with asuitable “protecting group” or “protective group”. A comprehensive listof suitable protective groups can be found in T. W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, Inc. 1991, thedisclosure of which is incorporated herein by reference in its entirety.The protected derivatives of compounds of the Invention can be preparedby methods well known in the art.

Methods for the preparation and/or separation and isolation of singlestereoisomers from racemic mixtures or non-racemic mixtures ofstereoisomers are well known in the art. For example, optically active(R— and (S)— isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. Enantiomers (R— andS-isomers) may be resolved by methods known to one of ordinary skill inthe art, for example by: formation of diastereoisomeric salts orcomplexes which may be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which may be separated, forexample, by crystallization, selective reaction of one enantiomer withan enantiomer-specific reagent, for example enzymatic oxidation orreduction, followed by separation of the modified and unmodifiedenantiomers; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support, such as silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where a desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step may be required to liberate the desired enantiomeric form.Alternatively, specific enantiomer may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents or by converting on enantiomer to the other by asymmetrictransformation. For a mixture of enantiomers, enriched in a particularenantiomer, the major component enantiomer may be further enriched (withconcomitant loss in yield) by recrystallization.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

The chemistry for the preparation of the compounds of this invention isknown to those skilled in the art. In fact, there may be more than oneprocess to prepare the compounds of the invention. The followingexamples illustrate but do not limit the invention. All references citedherein are incorporated by reference in their entirety.

SYNTHETIC EXAMPLESN-(2-((3-((9H-Purin-6-ylamino)rnethyl)-8-methylquinolin-2-yl)(methylamino)ethyl)-N-methyl-2-(1H-1,2,3-triazol-1-yl)acetamide(7)

2-Chloro-3-(chloromethyl)-8-methylquinoline (2)

To a stirred solution of 2-chloro-8-methylquinoline-3-carboxaldehyde (1,7.59 g, 36.9 mmol) in THF (150 mL) was added NaBH₄ (1.40 g, 37.0 mmol)and the reaction mixture was stirred at rt for 2 h. The reaction mixturewas concentrated under reduced pressure and the residue was trituratedwith satd. NaHCO₃ (aq., 200 mL). Precipitates were collected byfiltration, washed with H₂O, and dried under high vacuum to give thealcohol (7.47 g, 97%) as a white solid. MS (EI) for C₁₁H₁₀ClNO, found208 (MH⁺).

To a stirred suspension of the alcohol obtained above (7.47 g, 36.0mmol) in CHCl₃ (150 mL) was added SOCl₂ (13.1 ml, 180 mmol) slowly andthe resulting mixture was stirred at rt for 3 h. The reaction mixturewas carefully quenched with H₂O (10 mL), diluted with satd. NaHCO₃ (aq.,200 mL), and the separated aqueous layer was extracted with CH₂Cl₂ (200mL). The combined extracts were dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give2-chloro-3-(chloromethyl)-8-methylquinoline (2, 8.01 g, 98%) ascolorless oil. MS (EI) for C₁₁H₉Cl₂N, found 226 (MH⁺).

1 (2-Chloro-8-methylquinoline-3-yl)methanamine (3)

To a stirred solution of 2 (8.01 g, 35.4 mmol) in DMSO (150 mL) wasadded NaN₃ (4.61 g, 70.9 mmol) portionwise and the resulting mixture wasstirred at rt for 4 h. The reaction mixture was diluted with EtOAc (300mL)/H₂O (200 mL). The separated organic layer was washed with brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to afford the azide (7.66 g, 32.9 mmol). MS (EI) for C₁₁H₉ClN₄,found 233 (MH⁺).

To a stirred solution of the azide in THF (150 mL)/H₂O (20 mL) was addedPh₃P (12.9 g, 49.2 mmol) and the reaction mixture was stirred at rt for4 h at which time it was diluted with 1N HCl (150 mL)/CH₂Cl₂ (300 mL).The separated aqueous layer was washed with CH2Cl₂ (100 mL) and basifiedwith 1N NaOH to pH>10. The precipitated product 3 (5.12 g) was collectedby filtration, washed with H₂O, and dried under high vacuum. Thefiltrates were extracted with CH₂Cl₂ (3×100 mL). The combined extractswere dried over anhydrous sodium sulfate and concentrated under reducedpressure to give an additional aliquot of the product (0.77 g). Thecombined yield was 87% (5.89 g). MS (EI) for C₁₁H₁₁ClN₂, found 207(MH⁺).

N-((2-Chloro-8-methylquinolin-3-yl)methyl)-9H-purin-6-amine (4)

A mixture of 3 (620 mg, 3.00 mmol), 6-chloropurine (487 mg, 3.15 mmol)and Hunig's base (0.627 mL, 3.60 mmol) was stirred 1 h at 80° C. in EtOH(30 mL). The precipitate was filtered and the solid was washed withwater and EtOH to give 4 (726 mg, 75%) MS (EI) for _(C) ₁₆H₁₃ClN₆, found325 (MH+).

N¹-(3-((9H-Purin-6-ylamino)methyl)-8-methylquinolin-2-yl)-N¹,N²-dimethylethane-1,2-diamine (5)

A mixture of 4 (187 mg, 0.58 mmol) and N,N′-dimethylethylenediamine(0.624 mL, 5.8 mmol) in DMA (1.5 ml) was stirred at 140° C. for 1.5 h.The reaction mixture was concentrated under reduced pressure and theresidue was purified by flash chromatography to give 5 (165 mg, 76%). MS(EI) for C₂₀H₂₄N₈, found 377 (MH+).

N-(2-((3-((9H-Purin-6-ylamino)methyl)-8-methylquinolin-2-yl)(methylamino)ethyl)-N-methyl-2-(1H-1,2,3-triazol-1-yl)acetamide(7)

To a stirred mixture of 5 (65 mg, 0.173 mmol), 1-1,2,3-triazoleaceticacid (6, 22 mg, 0.173 mmol), and Hunig's base (0.091 mL, 0.522 mmol) inDMF (2 ml) was added HATU (66 mg, 0.174 mmol) and the reaction mixturewas stirred for 30 min. The crude mixture was directly purified by prep.HPLC to give 7 (39 mg, 46%). ¹H-NMR (400 MHz, d6-DMSO): δ13.0 (s, 1H),8.34 (bs, 1H), 8.16-8.11 (m, 2H), 8.00-7.95 (m, 2H), 7.71 (s, 1H),7.55-7.42 (m, 2H), 7.19 (q, 1H), 5.51-5.43 (2s, 2H), 4.86-4.83 (m, 2H),3.81-3.52 (m, 4H), 3.13-3.12 (2s, 3H), 3.04-2.97 (2s, 3H), 2.64-2.63(2s, 3H). MS (EI) for C₂₄H₂₇N₁₁O, found 486 (MH+).

In a similar manner, the following compounds were prepared:

N,8-dimethyl-N-[(1-methylpiperidin-4-yl)methyl]-3-[(9H-purin-6-ylthio)methyl]quinolin-2-amine(CMPD 1);

3-[(6-amino-9H-purin-9-yl)methyl]-N,8-dimethyl-N-[(1-methylpyrrolidin-2-yl)methyl]quinolin-2-amine(CMPD 2);

3-[(6-amino-9H-purin-9-yl)methyl]-N,8-dimethyl-N-[(1-methylpiperidin-2-yl)methyl]quinolin-2-amine(CMPD 3);

3-[(6-amino-9H-purin-9-yl)methyl]-N,8-dimethyl-N-[(1-methylpiperidin-4-yl)methyl]quinolin-2-amine(CMPD 4);

N-([2-(2-chlorophenyl)-8-methylquinolin-3-yl]methyl)-2,3-dihydro-1,4-benzodioxin-5-amine(CMPD 5);

N-{[8-methyl-2-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)quinolin-3-yl]methyl}-9H-purin-6-amine(CMPD 12);

9-{[8-methyl-2-(octahydroisoquinolin-2(1H)-yl)quinolin-3-yl)methyl}-9H-purin-6-amine(CMPD 13);

9-{[2-(3,4-dihydroisoquinolin-2(1H)-yl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine(CMPD 14);

N-{[2-(3,4-dihydroisoquinolin-2(1H)-yl)-8-methylquinolin-3-yl)methyl}-9H-purin-6-amine(CMPD 19);

N,8-dimethyl-N4-(methyloxy)ethyl]-3-[(9H-purin-6-ylamino)methyl]quinolin-2-amine(CMPD 25);

N-butyl-N,8-dimethyl-3-[(9H-purin-6-ylamino)methyl]quinolin-2-amine(CMPD 26);

N-[(8-methyl-2-piperidin-1-ylquinolin-3-yl)methyl]-9H-purin-6-amine(CMPD 27);

N-{2-[{3-[(6-amino-9H-purin-9-yl)methyl]-8-methylquinolin-2-yl}(methyl)amino]ethyl}-N-methyl-2-(1H-pyrazol-1-yl)acetamide(CMPD 28);

N,8-dimethyl-N-[(1-methylpiperidin-3-yl)methyl]-3-[(9H-purin-6-ylamino)methyl]quinolin-2-amine(CMPD 32);

N,8-dimethyl-N-[(1-methylpiperidin-4-yl)methyl]-3-(9H-purin-6-ylamino)methyl]quinolin-2-amine(CMPD 33);

N-{2-[{3-[(6-amino-9H-purin-9-yl)methyl]-8-methylquinolin-2-yl)}(methyl)amino]ethyl}-N-methyl-2-(1H-1,2,3-triazol-1-yl)acetamide(CMPD 34);

N,N′-dimethyl-N-{8-methyl-3-[(9H-purin-6-ylamino)methyl]quinolin-2-yl}ethane-1,2-diamine(CMPD 36);

N-[(8-methyl-2-piperazin-1-ylquinolin-3-yl)methyl]-9H-purin-6-amine(CMPD 37);

N,8-dimethyl-N-[(1-methylpiperidin-2-yl)methyl]-3-[(9H-purin-6-ylamino)methyl]quinolin-2-amine(CMPD 38);

3-iodo-1-{1-[3-(2-methylphenyl)quinolin-2-yl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine(CMPD 117);

3-iodo-1-{[5-methyl-3-(2-methylphenyl)quinolin-2-yl]methyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine(CMPD 119);

9-{[3-(2-methylphenyl)naphthalen-2-yl]methyl)-9H-purin-6-amine (CMPD120);

3-iodo-1-{[8-methyl-2-(2-methylphenyl)quinolin-3-yl]methyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine(CMPD 134);

3-iodo-N-{[8-methyl-2-(2-methylphenyl)quinolin-3-yl]methyl}-1H-pyrazolo[3,4-c]pyrimidin-4-amine(CMPD 135);

3-bromo-N-{[3-(2-methylphenyl)quinolin-2-yl]methyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine(CMPD 141);

N-{[2-(4-acetylpiperazin-1-yl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine(CMPD 143);

N-{[2-(4-ethylpiperazin-1-yl)-8-methylquinolin-3-yl]methyl)-9H-purin-6-amine(CMPD 144);

3-iodo-1-{[3-(2-methylphenyl)quinolin-2-yl]methyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine(CMPD 145);

N-{[8-methyl-2-(4-methyl-1,4-diazepan-1-yl)quinolin-3-yl]methyl1-9H-purin-6-amine (CMPD 146);

N-{3-[(6-amino-9H-purin-9-yl)methyl]-8-methylquinolin-2-yl}-N,N′-dimethylethane-1,2-diamine(CMPD 149);

9-{[8-methyl-2-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)quinolin-3-yl]methyl}-9H-purin-6-amine(CMPD 150);

N-{1-[2-(2-chlorophenyl)-8-methylquinolin-3-yl]ethyl}-9H-purin-6-amine(CMPD 152);

N-{3-[(6-amino-9H-purin-9-yl)methyl]-8-methylquinolin-2-yl}methanesulfonamide(CMPD 153);

N-{[2-(2-chlorophenyl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine(CMPD 154);

N-{[3-(2-methylphenyl)quinolin-2-yl]methyl}-9H-purin-6-amine (CMPD 155);

N-{3-[(6-amino-9H-purin-9-yl)methyl]-8-methylquinolin-2-yl)benzenesulfonamide(CMPD 156);

2-[(6-amino-9H-purin-9-yl)methyl]-3-(2-methylphenyl)thieno[3,2-d]pyrimidin-4(3H)-one(CMPD 162);

3-(2-methylphenyl)-2-[(7H-purin-6-ylthio)methyl]thieno[3,2-d]pyrimidin-4(3H)-one(CMPD 163);

3-[(6-amino-9H-purin-9-yl)methyl]-8-methyl-N-(1-methylpiperidin-4-yl)quinolin-2-amine(CMPD 164);

3-[(6-amino-9H-purin-9-yl)methyl]-8-methyl-N-(tetrahydro-2H-pyran-4-yl)quinolin-2-amine(CMPD 165);

9-{[2-(4-acetylpiperazin-1-yl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine(CMPD 166);

3-[(6-amino-9H-purin-9-yl)methyl]-8-methyl-N-[2-(methyloxy)ethyl]quinolin-2-amine(CMPD 167);

9-{[4-methyl-3-(2-methylphenyl)quinolin-2-yl]methyl}-9H-purin-6-amine(CMPD 168);

7-{[4-methyl-3-(2-methylphenyl)quinolin-2-yl]methyl}-7H-purin-6-amine(CMPD 169);

9-{[8-methyl-2-(2-methylpyrrolidin-1-yl)quinolin-3-yl]methyl}-9H-purin-6-amine(CMPD 170);

9-[(8-methyl-2-pyrrolidin-1-ylquinolin-3-yl)methyl]-9H-purin-6-amine(CMPD 171);

9-[(8-methyl-2-piperazin-1-ylquinolin-3-yl)methyl]-9H-purin-6-amine(CMPD 172);

9-{[8-methyl-2-(4-methylpiperazin-1-yl)quinolin-3-yl]methyl}-9H-purin-6-amine(CMPD 173);

9-[(8-methyl-2-morpholin-4-ylquinolin-3-yl)methyl}-9H-purin-6-amine(CMPD 177);

7-{[3-(2-methylphenyl)quinolin-2-yl]methyl}-7H-purin-6-amine (CMPD 178);

9-{[3-(2-methylphenyl)quinolin-2-yl]methyl}-9H-purin-6-amine (CMPD 179);

9-{[2-(2,3-dimethylphenyl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine(CMPD 180);

9-{[2-(2,5-dimethylphenyl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine(CMPD 181);

9-({8-methyl-2-[2-(trifluoromethyl)phenyl]quinolin-3-yl}methyl)-9H-purin-6-amine(CMPD 182);

9-{[8-methyl-2-(3-methylphenyl)quinolin-3-yl]methyl}-9H-purin-6-amine(CMPD 183);

9-{[8-methyl-2-(3-{[2-(methyloxy)ethyl]oxy}phenyl)quinolin-3-yl]methyl}-9H-purin-6-amine(CMPD 184);

9-({8-methyl-2-[3-(methyloxy)phenyl]quinolin-3-yl}methyl)-9H-purin-6-amine(CMPD 185);

9-({2-[2-(ethyloxy)phenyl]-8-methylquinolin-3-yl}methyl)-9H-purin-6-amine(CMPD 186);

9-{[2-(2-chlorophenyl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine(CMPD187);

8-methyl-2-(2-methylphenyl)-3-[(9H-purin-6-ylthio)methyl]quinoline (CMPD188);

9-{[8-methyl-2-(2-methylphenyl)quinolin-3-yl]methyl}-9H-purin-6-amine(CMPD 189);

9-{[3-(2-methylphenyl)quinoxalin-2-yl]methyl}-9H-purin-6-amine (CMPD190); and

9-{[2-(2-methylphenyl)quinolin-3-yl]methyl}-9H-purin-6-amine (CMPD 191).

3-Amino-N-{[5-methyl-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl}pyrazine-2-earboxamide(13)

2-Amino-6-methyl-N-o-tolylbenzamide 2-amino-6-methylbenzoate (9)

Thionyl chloride (20.0 mL, 274 mmol) and 2-amino-6-methylbenzoic acid(8, 10.0 g, 66.2 mmol) was added to toluene (100 mL) and the mixture washeated to 110° C. for 1 h then concentrated. The crude acid chloride wasdissolved in THF (100 mL), cooled to 0° C., and o-toluidine (21 mL, 196mmol) was added slowly. The reaction mixture was heated to 80° C. andthe product precipitated out over 2 h. The reaction mixture was thenquenched with K₂CO₃ (10%, aq.), extracted with EtOAc, diluted withNa₂SO₄, filtered, and concentrated. The product was recrystallized fromDCM/hexanes to provide 9 (14.7 g, 92% over 2 steps) as an off-whitesolid.

2-(Chloromethyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one (10)

To 9 (13.7 g, 57.0 mmol) in AcOH (50 mL) was added 2-chloroacetylchloride (13.6 mL, 171 mmol) and the reaction mixture was heated to120′C. After 15 min the reaction mixture was diluted with H₂O andextracted with EtOAc (2×), The organic layer was washed with H₂O (2×),washed with brine, dried with Na₂SO₄, filtered, and concentrated. Flashcolumn chromatography (Hexanes to 3:1 Hexanes/EtOAc) followed bytrituration from EtOAc provided 10(5.13 g, 26%) as a colorless solid.

2-(Aminomethyl)-5-methyl3-o-tolylquinazolin-4(3H)-one (11)

To 10 (1.00 g, 3.36 mmml) in DMF (10 mL) was added sodium azide (0.4366.71 mmol) and the mixture was stirred at ambient temperature for 15min. The crude reaction mixture was then diluted with methanol (20 mL)and ammonium formate (1.0 g, 16 mmol) followed'by Pd/C (10%. 200 mg) wasadded. The reaction mixture was heated to 80° C. for 30 min at whichtime it was cooled to ambient temperature, filtered through Celite, anddiluted with. EtOAc and H₂O. The organic layer was washed with H₂O,brine, dried with Na₂SO₄, filtered, and concentrated. The crude 11obtained in this manner was carried forward without furtherpurification.

3-Amino-N-{[5-methyl-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl}pyrazine-2-earboxamide(13)

3-Aminopyrazine-2-carboxylic acid (12, 39.0 mg, 0.280 mmol), Hunig'sbase (0.1 mL, 0.6 mmol), and HATU (108 mg, 0.280 mmol) were dissolved inDMF (0.5 mL) and the crude 11 obtained above (39.0 mg, 0.140 mmol) wasadded. The resulting reaction mixture was stirred at ambient temperaturefor 20 min then diluted with methanol and purified by preparative HPLCto give 13 (39.9 mg, 71%. ¹H-NMR (400 MHz, d6-DMSO); δ9.07 (t, 1H), 8.26(s, 1H), 7.91 (s, 1H), 7.79-7.63 (m, 1H), 7,57-7.38 (m, 5H), 7.34 (d,1H), 4.11 (dd, 1H), 3.81 (dd, 1H), 2.75 (s, 3H), 2.11 (s, 3H). MS (EI)for C₂₂H₂₀N₆O₂, found 401 (MH+).

In a similar manner, the following compounds were prepared:

1-[2-(2-chloropheriyl)-8-methylquinolin-3-yl]-N-{[3-(methyloxy)phenyl]methyl}methanamine(CMPD 6);

3-({[2-chloro-4-(methyloxy)phenyl]oxy}methyl)-2-(2-chlorophenyl)-8-methylquinoline(CMPD 7);

3-[(1,3-benzodioxol-5-yloxy)methyl]-2-(2-chlorophenyl)-8-methylquinoline(CMPD8);

N-{[2-(2-chlorophenyI)-8-methylquinolin-3-yl]methyl}-3,5-bis(methyloxy)aniline(CMPD 9);

N-{[2-(2-chlorophenyl)-8-methylquinolin-3-yl]methyl}-3,4-bis(methyloxy)aniline(CMPD 10);

N-{[2-(2-chlorophenyl)-8-methylquinolin-3-yl]methyl}-2-(methyloxy)aniline (CMPD 11);

3-({[3,5-bis(methyloxy)pheny]oxy}methyl)-2-(2-chlorophenyl)-8-methylquinoline(CMPD 15);

2-(2-chlorophenyl)-8-methyl-3-({[4-(methyloxy)phenyl]oxy}methyl)quinoline(CMPD 16);

2-(2-chlorophenyl)-8-methyl-3-(1-{[4-(methyloxy)phenyl]oxy}ethyl)quinoline(CMPD 17);

N-{[2-2-chlorophenyl)-8-methylquinolin-3-yl]methyl}-3-(methyloxy)aniline(CMPD 18);

N,N′-dimethyl-N-[8-methyl-3-({[4-(methyloxy)phenyl]amino}methyl)quinolin-2-yl]ethane-1,2-diamine(CMPD 20);

N,N′-dimethyl-N-[8-methyl-3-(morpholin-4-ylmethyl)quinolin-2-yl]ethane-1,2-diamine(CMPD 21);

N,N′-dimethyl-N-[8-methyl-3-({[3-(methyloxy)phenyl]oxy)methyl)quinolin-2-yl]ethane-1,2-diamine(CMPD 22);

N,N′-dimethyl-N-[8-methyl-3-({[4-(methyloxy)phenyl]oxy}methyl)quinolin-2-yl]ethane-1,2-diamine(CMPD 23);

N,N′-dimethyl-N-[8-methyl-3-({[3-(methyloxy)phenyl]amino}methyl)quinolin-2-yl]ethane-1,2-diamine(CMPD 24);

N-{3-[5-(3-aminopyrazin-2-yl)-1,3,4-oxadiazol-2-yl]-8-methylquinolin-2-yl}-N,N′-dimethylethane-1,2-diamine(CMPD 29);

3-amino-N-[(8-methyl-2-{methyl[(1-methylpiperidin-3-yl)methyl]amino}quinolin-3-yl]methyl]pyrazine-2-carboxamide(CMPD 30);

3-amino-N-[(8-methyl-2-{methyl[(1-methylpiperidin-4-yl)methyl]amino}quinolin-3-yl)methyl]pyrazine-2-carboxamide(CMPD 31);

3-amino-N-[(8-methyl-2-{methyl[(1-methylpiperidin-2-yl)methyl]amino}quinolin-3-yl)methyl]pyrazine-2-carboxamide(CMPD 39);

N-methyl-N′-[(8-methyl-2-{methyl[2-(methylamino)ethyl]amino}quinolin-3-yl)methyl]cyclopropane-1,1-dicarboxamide(CMPD 40);

3-{[3-(4-acetylpiperazin-1-yl)quinoxalin-2-yl]amino}benzamide (CMPD 41);

3-amino-N-{[8-methyl-2-(methyl[2-[methyl(1H-tetrazol-1-ylacetyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 42);

3-amino-N-({2-[(2-{[(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetyl](methyl)amino)ethyl}(methyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 43);

3-amino-N-{[2-(3-{[2-(dimethylamino)-2-oxoethyl]amino}pyrrolidin-1-yl)-8-methylquinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 44);

3-amino-N-[(8-methyl-2-{3-[(1H-1,2,3-triazol-1-ylacetyl)amino]pyrrolidin-1-yl}quinolin-3-yl)methyl]pyrazine-2-carboxamide(CMPD 45);

3-amino-N-({2-[bis(pyridin-3-ylmethyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 46);

3-amino-N-({2-[bis(pyridin-2-ylmethyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 47);

3-amino-N-[(5-chloro-3-{2-[(dimethylamino)methyl]phenyl}quinolin-2-yl)methyl]pyrazine-2-carboxamide(CMPD 48);

3-amino-N-{[8-methyl-2-(methyl{2-[methyl(1H-pyrazol-1-ylacetyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 49);

3-amino-N-{[2-(3-hydroxypropyl)-8-methylquinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 50);

3-amino-N-{[8-methyl-2-(methyl{2-[(1H-1,2,3-triazol-1-ylacetyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 51);

3-amino-N-[(3-{2-[(dimethylamino)methyl]phenyl}-5-methylquinolin-2-yl)methyl]pyrazine-2-carboxamide(CMPD 52);

3-amino-N-({2-[4-(1H-benzimidazol-1-ylacetyl)-1,4-diazepan-1-yl]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 53);

3-amino-N-({2-[4-(1H-imidazol-1-ylacetyl)-1,4-diazepan-1-yl]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 54);

3-amino-N-[(8-methyl-2-{4-[(2-methyl-1H-imidazol-1-yl)acetyl]-1,4-diazepan-1-yl}quinolin-3-yl)methylipyrazine-2-carboxamide(CMPD 55);

3-amino-N-[(3-{2-[(dimethylamino)carbonyl]phenyl}quinolin-2-yl)methyl]pyrazine-2-carboxamide(CMPD 56);

3-amino-N-[(8-methyl-2-{4-[(1-methyl-1H-pyrrol-2-yl)methyl]-1,4-diazepan-1-yl}quinolin-3-yl)methyl]pyrazine-2-carboxamide(CMPD 57);

3-amino-N-[(8-methyl-2-{4-[(5-methylfuran-2-yl)methyl]-1,4-diazepan-1-yl}quinolin-3-yl)methyl]pyrazine-2-carboxamide(CMPD 58);

3-amino-N-({3-[2-(piperidin-1-ylmethyl)phenyl]quinolin-2-yl}methyl)pyrazine-2-carboxamide(CMPD 59);

3-amino-N-({8-methyl-2-[4-(1H-1,2,3-triazol-1-ylacetyl)-1,4-diazepan-1-yl]quinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 60);

3-amino-N-({8-methyl-2-[4-(2H-1,2,3-triazol-2-ylacetyl)-1,4-diazepan-1-yl]quinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 61);

3-amino-N-[(8-methyl-2-{4-[(1-methyl-1H-imidazol-2-yl)methyl]-1,4-diazepan-1-yl}quinolin-3-yl)methyl]pyrazine-2-carboxamide(CMPD 62);

3-amino-N-[(8-methyl-2-{4-[(1-methyl-1H-imidazol-5-yl)methyl]-1,4-diazepan-1-yl}quinolin-3-yl)methyl]pyrazine-2-carboxamide(CMPD 63);

3-amino-N-[(8-methyl-2-{(pyridin-3-ylmethyl)-1,4-diazepan-1-yl]quinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 64);

3-amino-N-({8-methyl-2-[4-(pyridin-4-ylmethyl)-1,4-diazepan-1-yl]quinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 65);

3-amino-N-[(2-{4-[2-(dimethylamino)-2-oxoethyl]-1,4-diazepan-1-yl}-8-methylquinolin-3-yl)methyl]pyrazine-2-carboxamide(CMPD 66);

3-amino-N-{[8-methyl-2-(methyl{2-[methyl(1-propyl-D-prolyl)pamino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 67);

3-amino-N-{[8-methyl-2-(methyl{2-methyl(pyridin-2-ylmethyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 68);

3-amino-N-[(3-{3-[(dimethylamino)methyl]phenyl}quinolin-2-yl)methyl]pyrazine-2-carboxamide(CMPD 69);

3-amino-N-({3-[2-(morpholin-4-ylmethyl)phenyl]quinolin-2-yl}methyl)pyrazine-2-carboxamide(CMPD 70);

3-amino-N-({3-[4-(morpholin-4-ylmethyl)phenyl]quinolin-2-yl}methyl)pyrazine-2-carboxamide(CMPD 71);

3-amino-N-({3-[4-(morpholin-4-ylmethyl)phenyl]quinolin-2-yl}methyl)pyrazine-2-carboxamide(CMPD 72);

3-amino-N-({8-methyl-2-[methyl(2-{methyl[1-(1-methylethyl)-D-proly]amino}ethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 73);

2-amino-N-{[3-(2-methylphenyl)quinolin-2-yl]methyl}pyrimidine-5-carboxamide(CMPD 74);

3-amino-N-{1-[3-(2-methylphenyl)quinolin-2-yl]ethyl}pyrazine-2-carboxamide(CMPD 75);

3-amino-N-({8-methyl-2-[methyl(2-{methyl[2-(methylamino)-2-oxoethyl]amino}ethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 76);

3-amino-N-{[8-methyl-2-(methyl{2-[methyl(2-morpholin-4-yl-2-oxoethyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 77);

3-amino-N-{[8-methyl-2-(methyl{2-[methyl(pyrazin-2-ylcarbonyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 78);

3-amino-N-{[8-methyl-2-(methyl{2-[methyl(pyridin-4-ylcarbonyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 79);

3-amino-N-{[8-methyl-2-(methyl{2-[methyl(pyridin-3-ylcarbonyl)amino]ethyl}amino)quinolin-3-yl[methyl}pyrazine-2-carboxamide(CMPD 80);

3-amino-N-{[8-methyl-2-(methyl{2-[methyl(pyridin-2-ylcarbonyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 81);

3-amino-N-({8-methyl-2-[methyl(2-{methyl[(4-methylphenyl)sulfonyl]amino}ethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 82);

3-amino-N-{[8-methyl-2-(methyl{2-[methyl(pyridin-3-ylmethyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 83);

3-amino-N-({2-[{2-[(cyanomethyl)(methyl)amino]ethyl}(methyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 84);

3-amino-N-({2-[{2-[(1H-imidazol-1-ylacetyl)(methyl)amino]ethyl}(methyl)amino]-8-methylquinolin-3-yl}methyppyrazine-2-carboxamide(CMPD 85);

3-amino-N-({8-methyl-2-[methyl(2-{methyl[(2-methyl-1H-imidazol-1-yl)acetyl]amino}ethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 86);

3-amino-N-({8-methyl-2-[methyl(pyridin-3-ylmethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 87);

3-amino-N-({8-methyl-2-[methyl(2-pyridin-2-ylethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 88);

3-amino-N-({2-[(2-{(2-(dimethylamino)-2-oxoethyl]methyl)amino}ethyl)(methyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 89);

3-amino-N-{[8-methyl-2-(methyl{2-[methyl(pyrazin-2-yl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 90);

3-amino-N-{[3-(1,3-thiazol-4-yl)quinolin-2-yl]methyl}pyrazine-2-carboxamide(CMPD 91);

3-amino-N-[(3-{2-[(dimethylamino)methyl]phenyl}quinolin-2-yl)methyl]pyrazine-2-carboxamide(CMPD 92);

3-amino-N-[(3-bromoquinolin-2-yl)methyl]pyrazine-2-carboxamide (CMPD93);

3-amino-N-{[8-methyl-2-(methyl{2-[methyl(2H-1,2,3-triazol-2-ylacetyl)amino]ethyl}amino)quinolin-3-yl]methyl)pyrazine-2-carboxamide(CMPD 94);

3-amino-N-({8-methyl-2-[(pyridin-3-ylmethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 95);

3-amino-N-({8-methyl-2-[(2-pyridin-2-ylethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 96);

3-amino-N-({8-methyl-2-[(2-pyridin-3-ylethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 97);

3-amino-N-({8-methyl-2-[methyl(1-methylpyrrolidin-3-yl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 98);

3-amino-N-({8-methyl-2-[methyl(1-methylpiperidin-4-yl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 99);

3-amino-N-{[8-methyl-2-(methyl{2-methyl(1H-1,2,3-triazol-1-ylacetyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 100);

3-amino-N-{[8-methyl-2-(methyl{2-[methyl(methylsulfonyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 101);

3-amino-N-{[8-methyl-2-(methyl{2-methyl(D-prolyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 102);

3-amino-N-{[8-methyl-2-(methyl{2-methyl(L-prolyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 103);

3-amino-N-[(8-methyl-2-{methyl[2-(methyloxy)ethyl]amino}quinolin-3-yl)methyl]pyrazine-2-carboxamide(CMPD 104);

3-amino-N-{[3-(2-methylphenyl)quinolin-2-yl]methyl}-5-morpholin-4-ylpyrazine-2-carboxamide(CMPD 105);

3-amino-5-(methyloxy)-N-{[3-(2-methylphenyl)quinolin-2-yl]methyl}pyrazine-2-carboxamide(CMPD 106);

3-amino-5-chloro-N-{[3-(2-methylphenyl)quinolin-2-yl]methyl}pyrazine-2-carboxamide(CMPD 107);

4-amino-N-{[3-(2-methylphenyl)quinolin-2-yl]methyl}pyrimidine-5-carboxamide(CMPD 108);

3-amino-N-{[8-methyl-2-(methyl{2-[methyl(pyrrolidin-1-ylacetyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 109);

3-amino-N-({8-methyl-2-[methyl(2-{methyl[(1-methyl-1H-imidazol-5-yl)carbonyl]amino}ethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 110);

3-amino-N-{[2-(1H-imidazol-1-yl)-8-methylquinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 111);

3-amino-N-{[2-(1H-benzimidazol-1-yl)-8-methylquinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 112);

3-amino-N-{[8-methyl-2-(methyl{2-[methyl(1-methyl-L-prolyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 113);

3-amino-N-({2-[{2-[(N,N-dimethylglycyl)(methyl)amino]ethyl}(methyl)amino]-8-methylquinolin-3-yl)methyl)pyrazine-2-carboxamide(CMPD 114);

3-amino-N-({2-[{2-[glycyl(methyl)amino]ethyl}(methypamino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 115);

3-amino-N-{[8-methyl-2-(methyl{2-[methyl(N-methylglycyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 116);

3-amino-N-{[5-methyl-3-(2-methylphenyl)quinolin-2-yl]methyl}pyrazine-2-carboxamide(CMPD 118);

3-amino-N-({2-[(2-hydroxyethyl)(methyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 121);

3-amino-N-[(8-methyl-2-{[2-(methylamino)ethyl]oxy}quinolin-3-yl)methyl]pyrazine-2-carboxamide(CMPD 122);

3-amino-N-({2-{[(2R,5S)-2,5-dimethylpiperazin-1-yl]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 123);

N-{[2-(4-acetylpiperazin-1-yl)-8-methylquinolin-3-yl]methyl}-3-aminopyrazine-2-carboxamide(CMPD 124);

3-amino-N-({2-[(2-hydroxyethyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 125);

1,1-dimethylethyl{1-[3-({[(3-aminopyrazin-2-yl)carbonyl]amino}methyl)-8-methylquinolin-2-yl]piperidin-4-yl}methylcarbamate(CMPD 126);

3-amino-N-([2-[4-(dimethylamino)piperidin-1-yl]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 127);

3-amino-N-[(2-{[2-(dimethylamino)ethyl](methyl)amino}-8-methylquinolin-3-yl)methyl]pyrazine-2-carboxamide(CMPD 128);

3-amino-N-[(2-{[2-(dimethylamino)ethyl]amino}-8-methylquinolin-3-yl)methyl]pyrazine-2-carboxamide(CMPD 129);

3-amino-N-[(8-methyl-2-(methyl[2-(methylamino)ethyl]amino}quinolin-3-yl)methyl]pyrazine-2-carboxamide(CMPD 130);

3-amino-N-[(8-methyl-2-piperazin-1-ylquinolin-3-yl)methyl]pyrazine-2-carboxamide(CMPD 131);

N˜5˜{[3-(2-methylphenyl)quinolin-2-yl]methyl{pyrimidine-4,5-diamine(CMPD 132);

3-amino-N-[(8-methyl-2-{methyl[3-(methylamino)propyl]amino}quinolin-3-yl)methyl]pyrazine-2-carboxamide(CMPD 133);

3-amino-N-({2-[{3-[(N,N-dimethylglycyl)(methyl)amino]propyl}(methyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 136);

3-amino-N-({(2-[4-(N,N-dimethylglycyl)-1,4-diazepan-1-yl]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide(CMPD 137);

3-amino-N-[(2-{[3-(dimethylamino)propyl]amino}-8-methylquinolin-3-yl)methyl]pyrazine-2-carboxamide (CMPD 138);

3-amino-N-{[2-(1,4-diazepan-1-yl)-8-methylquinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 139);

3-amino-N-{[8-methyl-2-(4-methyl-1,4-diazepan-1-yl)quinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 140);

3-amino-N-{[3-(2-methylphenyl)quinolin-2-yl]methyl}pyrazine-2-carboxamide(CMPD 142);

3-amino-N-[(8-methyl-2-piperidin-1-ylquinolin-3-yl)methyl]pyrazine-2-carboxamide(CMPD 147);

3-amino-N-{[2-(2-chlorophenyl)-8-methylquinolin-3-yl]methyl}pyrazine-2-carboxamide(CMPD 148);

N-{[5-methyl-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl}-3-morpholin-4-ylpyrazine-2-carboxamide(CMPD 151);

2-(2-aminoethyl)-5-methyl-3-(2-methylphenyl)quinazolin-4(3H)-one (CMPD157);

3-({[3,5-bis(methyloxy)phenyl]methyl}oxy)-8-methyl-2-(2-methylphenyl)quinoline(CMPD 158);

3-chloro-N-{[5-methyl-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl}pyrazine-2-carboxamide(CMPD 159);

3-amino-6-bromo-N-{[5-methyl-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl}pyrazine-2-carboxamide(CMPD 160);

3-amino-N-{[5-methyl-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl}pyridine-2-carboxamide(CMPD 161);

2-amino-N-{[5-methyl-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl}pyridine-4-carboxamide(CMPD 174); and2-amino-N-{[5-methyl-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl{pyridine-3-carboxamide(CMPD 176).

BIOLOGICAL EXAMPLES Example 1 Biochemical Assays

Kinase activity and compound inhibition were investigated using one ormore of the assay formats described below. The ATP concentrations usedin the various assays were approximately equal to or less than the K_(M)for each of the respective kinases. Dose-response experiments wereperformed using an intra-plate dilution scheme with 10 differentinhibitor concentrations in a 384-well microtiter plate. IC₅₀ valueswere calculated by nonlinear regression analysis using thefour-parameter equation listed below:

Y=min+(max−min)/(1+(X/IC ₅₀)^(N))   Equation 1

where Y is the observed signal, X is the inhibitor concentration, min isthe background signal in the absence of enzyme (0% enzyme activity), maxis the signal in the absence of inhibitor (100% enzyme activity), IC₅₀is the inhibitor concentration at 50% enzyme inhibition and N representsthe empirical Hill slope as a measure of cooperativity. Typically Nshould approximate unity. Curve fitting was performed using XLFit orActivityBase.

Luciferase-Coupled Chemiluminescence Assay Protocol

Kinase activity is measured as the percent of ATP consumed following thekinase reaction using luciferase-luciferin-coupled chemiluminescence.Reactions were conducted in 384 or 1536-well white medium bindingmicrotiter plates (Greiner). Kinase reactions were initiated bycombining test compounds, kinase, and ATP in a 20 μL volume (6 μL volumefor 1536-well plate). The reaction mixture was incubated at ambienttemperature for 2 h. Following the kinase reaction, a 20 μL (or 3 μL for1536-well plate) aliquot of KinaseGlo (Promega) was added and thechemiluminescence signal measured using an EnVision plate reader (PerkinElmer). Total ATP consumption was limited to 25-60% and the IC₅₀ valuescorrelate well with those determined by radiometric assays.

PI3K delta activities of the Compounds of Formula I are provided inTable 2.

TABLE 2 PI3K Dalta Activity of Compounds of Formula I Compound ActivityIC50 1 B 2 A 3 A 4 A 5 D 6 D 7 D 8 D 9 D 10 D 11 D 12 A 13 D 14 D 15 D16 D 17 D 18 D 19 D 20 D 21 D 22 D 23 D 24 D 25 A 26 B 27 B 28 A 29 D 30A 31 A 32 A 33 A 34 A 35 A 36 A 37 A 38 A 39 A 40 D 41 D 42 A 43 A 44 D45 D 46 C 47 D 48 A 49 A 50 D 51 B 52 A 53 D 54 D 55 D 56 C 57 D 58 D 59B 60 C 61 D 62 D 63 B 64 C 65 D 66 D 67 A 68 B 69 C 70 C 71 D 72 D 73 A74 D 75 C 76 B 77 B 78 D 79 B 80 C 81 C 82 D 83 A 84 B 85 A 86 A 87 B 88D 89 A 90 D 91 D 92 B 93 D 94 B 95 D 96 D 97 D 98 B 99 B 100 A 101 B 102B 103 B 104 D 105 D 106 D 107 D 108 D 109 B 110 B 111 C 112 D 113 B 114B 115 B 116 B 117 A 118 C 119 A 120 D 121 B 122 D 123 C 124 C 125 D 126D 127 D 128 A 129 D 130 C 131 D 132 D 133 B 134 A 135 B 136 A 137 C 138D 139 C 140 C 141 D 142 D 143 A 144 A 145 A 146 A 147 D 148 B 149 A 150D 151 D 152 A 153 D 154 A 155 B 156 D 157 D 158 D 159 D 160 D 161 D 162D 163 D 164 D 165 D 166 B 167 D 168 D 169 D 170 B 171 B 172 B 173 B 174D 175 A 176 D 177 B 178 B 179 D 180 D 181 B 182 B 183 C 184 C 185 C 186C 187 B 188 B 189 B 190 D 191 D A 0 < PI3K Delta Activity < 50 nM B 50 <PI3K Delta Activity < 250 nM C 250 < PI3K Delta Activity < 500 nM D 500< PI3K Delta Activity < 1500 nM

Reversibility of Inhibition

The reversibility of enzyme inhibition is evaluated for PI3K delta bymeasuring residual enzyme activity after dilution of an enzyme-inhibitorcomplex in saturating ATP. Inhibitor complexes were formed by incubatingPI3K delta (2 μM) and a compound of Formula I (2 μM) for 30 minutes atambient temperature. The EI complex is then serially diluted into bufferand allowed to reach equilibrium. Quantitative inhibition (approximately75%) of the EI complex is found by measuring enzyme activity withoutdilution into buffer. A 5 μL sample of each dilution is then transferredto a 384-well low-volume medium binding white plate and then a 5 μLaliquot of substrate (40 μM PIP₂) and 1 mM ATP is added to the plate.Following an incubation of the reaction (5-60 mins) a 10 μL aliquot ofADP-Glo Reagent #1 is added and incubated for 40 minutes. Finally, 10 μLof ADP-Glo Reagent #2 is added to the plate and following a 60 minuteincubation the reactions were read on the Envision Microplate Reader.

Mechanism of Kinase Inhibition

Compounds of Formula I listed in Table 1 are characterized forreversibility of binding, inhibition type, and K_(i) values. ATPvariation studies are conducted by determining IC₅₀ values for CompoundA against PI3Kdelta using increasing ATP concentrations. The assays areconducted by mixing 2 μL of PI3Kdelta with 0.1 μL of compound in a384-well low volume white medium binding plate. After a 15 minuteincubation, 2 μL of substrate (PIP₂) and ATP at varying concentrations(1500, 1000, 500, 250, 1μM final) are added to the plate. Followingincubation of the kinase reaction (15-120 minutes), 4 μL of ADP-Glo(Promega) Reagent #1 is added to the entire plate and incubated for 40minutes. Finally, 8 μL of ADP-Glo Reagent #2 is added to the entireplate, incubated for 60 minutes, and then the plate is read using anEnvision microplate reader. The resulting IC₅₀ values are plotted as afunction of ATP concentration, and K_(i) values are derived using thefollowing equation.

IC ₅₀ =K _(I) /K _(M) [ATP]+K _(I) +[E]/2   Equation 2

-   -   where [E] represents the concentration of enzyme.

Determination of K_(M) Value for ATP

The K_(M) value for ATP is determined using the ADP-GLO assay formatdescribed above. K_(M) for ATP is derived by varying ATP concentrations(ranging from 15 to 1600 μM) at a fixed PIP₂ concentration (50 μM).

Example 2 Cellular Assays Endogenous AKT^(T308) Phosphorylation ELISAAssay in Anti-IgM Stimulated Raji Cells

Raji cells (ATCC, CCL-86) are seeded at 1×10⁶ cells/well onto 96-wellplates (Corning, Costar 3960) in RPMI 1640 medium (ATCC, 30-2001)containing 10% FBS (Heat-Inactivated, Gibco, 10082), and 1%Penicillin/Streptomycin (Cellgro, 30-002-CI). Serial dilutions of testcompounds in a final concentration of 0.3% DMSO (vehicle)are added tothe cells and incubated for 90 min. Cells are stimulated with 0.25 μg/mLanti-IgM (Southern Biotech, 9023-01) for 30 min. Minimal signal wellsare cells treated with 0.3% DMSO without anti-IgM stimulation; maximalsignal wells are in 0.3% DMSO with anti-IgM stimulation. Afterstimulation, cells are spun down at 290×g for 4 min and immediatelylysed with 120 μL of cold lysis buffer (50 mM Tris-HCl, pH 7.6; 150 mMNaCl; 0.1% Triton X-100; 1 mM EDTA; Protease Inhibitor Cocktail (Roche,11697498001) and PhosSTOP (Roche, 04906837001)). To detectphospho-AKT^(T308) and total AKT, commercially available ELISA kits areused (Invitrogen, KHO0201 and KHO0101). 100 or 10 μL. of cell lysate istransferred to phospho-AKT^(T308) or total AKT plates, respectively. Anadditional 90 μL of lysis buffer is added to the total AKT plates.Plates are incubated overnight at 4° C. and washed four times with 200μL of manufacturer-provided ish buffer (Invitrogen, WB01). Plates areincubated with 100 μL of detection antibody solution for 1.5 h. Platesare ished four times with 200 μL of ish buffer, then incubated for I hwith secondary antibody using the corresponding buffer. Plates are ishedas above, followed by the addition of 100 μμL/well of StabilizedChromogen solution for 20 min. The reaction is stopped by adding 100 μLof Stop Solution. Absorbance at wavelength of 450 nm is measured using aspectrophotometer (Molecular Devices, SpectraMax Plus). Intra-wellnormalization is accomplished by dividing the phospho-AKT^(T308) ODvalues by the total AKT OD values. IC₅₀ values are then estimated bycomparing the values of compound-treated samples with averages of theaforementioned minimal and maximal signal condition wells.

Western Blot Profiling Analysis of Anti-igm-stimulated Raji Cells

1×10⁷ Raji cells (ATCC, CCL-86) are seeded in 14-mL round-bottom tubesin RPMI 1640 medium (ATCC, 30-2001) containing 10% FBS(Heat-Inactivated, Gibco, 10082), and 1% Penicillin/Streptomycin(Cellgro, 30-002-CI). Serial dilutions of test compound in a finalconcentration of 0.3% DMSO (vehicle) are added to the cells andincubated for 90 min followed by 0.25 μg/mL anti-IgM (Southern Biotech,9023-01) stimulation for 30 min. After stimulation, cells are spun downat 290×g for 4 min, washed once with cold phosphate-buffered saline(PBS; Cellgro, 21-030-CV) and immediately lysed with 120 μL of coldlysis buffer (50 mM Tris-HCl, pH 7.6; 150 mM NaCl; 0.1% Triton X-100; 1mM EDTA; Protease Inhibitor Cocktail (Roche 11697498001); and PhosSTOP(Roche, 04906837001)) for 30 min. Lysates are collected and cleared bycentrifugation at 17,800×g for 15 min. Protein concentrations aremeasured by the BCA method (Pierce, 23227). Lysates are mixed withNuPage LDS sample buffer (Invitrogen, NP0007) and Reducing Agent(Invitrogen, NP0004), then heated at 70° C. for 10 min. 26 μg protein isloaded onto NuPage 4-12% Bis-Tris gels (Invitrogen, NP0323). Proteinsare transferred to nitrocellulose membranes (Invitrogen, LC2001),blocked for 1 h in Odyssey Blocking Buffer (Li-Cor, 927-40000), andincubated at 4° C. overnight with the following antibodies diluted inOdyssey Blocking Buffer containing 0.1% Tween-20:Anti-phospho-AKT^(T308) (1:500, Cell Signaling Technology, 2965),Anti-phospho-AKT^(S473) (1:1,000, Cell Signaling Technology, 4060),Anti-AKT (1:2,000, R&D Systems, MAB 2055), Anti-phospho-PRAS40^(T246)(1:500, Cell Signaling Technology, 2640), anti-phospho-GSK31β^(S9)(1:500, Cell Signaling Technology, 9336), Anti-phospho-S6^(S240/244)(1:500, Cell Signaling Technology, 2215), Anti-S6 (1:1,000, CellSignaling Technology, 2217), Anti-GAPDH (1:100,000, AdvancedImmunochemical Inc, MAB6C5). Membranes are washed four times for 10 mineach with TBS-T buffer (50 mM Tris-HCl, pH 7.2; 150 mM NaCl; 0.1%Tween-20) and blotted with Goat anti-Mouse-IRDye680 (Li-Cor, 926-32220)and Goat anti-Rabbit-IRDye800 (Li-Cor, 926-32211) secondary antibodiesin Odyssey Blocking buffer containing 0.1% Tween-20 for 60 min at roomtemperature. Membranes are washed four times for 10 min each with TBS-Tbuffer and rinsed with PBS twice. The membranes are scanned using theOdyssey Scanner (Li-Cor) and the signal intensity of each band isquantified using ImageQuant (Molecular Devices). IC₅₀ values arecalculated based on the signal with compound treatment compared to thevehicle (DMSO) control.

Western Blot Analysis of Anti-igm-induced Akt Phosphorylation in HumanPeripheral Blood B-lymphocytes

Human primary B-lymphocytes (B cells, AllCells, PB010) are seeded at6×10⁵ cells/well onto 48-well cluster plates (Nunc 150687) in RPMI 1640medium (ATCC, 30-2001) containing 10% FBS (Heat Inactivated, Gibco,10082), 1% Penicillin/Streptomycin (Cellgro, 30-002-CI), 1% L-glutamine(Cellgro, 25-015-CI), and 50 μM β-mercaptoethanol (Gibco, 21985-023).Serial dilutions of test compound in a final concentration of 0.3% DMSO(vehicle) are added to the cells and incubated for 2 h followed by 10μg/mL anti-IgM (Southern Biotech, 9023-01) stimulation for 5 min. Afterstimulation, cells are centrifuged at 290×g for 4 min, washed once withcold phosphate-buffered saline (PBS; Cellgro, 21-030-CV) and immediatelylysed with 40 μL of cold lysis buffer (50 mM Tris-HCl, pH 8.0, 150 mMNaCl, 1% NP-40, 0.1% SDS, 0.5% sodium deoxycholate, 1 mM EDTA, 50 mMNaF, 1 mM sodium pyrophosphate, 1 mM sodium orthovanadate, 2 mMphenylmethylsulfonyl fluoride, 10 μg/mL aprotinin, 5 μg/mL leupeptin,and 5 μg/mL pepstatin A) for 30 min. Lysates are collected and clearedby centrifugation at 17,800×g for 15 min. Lysates are mixed with NuPageLDS sample buffer (Invitrogen NP0007) and Reducing Agent (Invitrogen,NP0004), then heated at 70° C. for 10 min. The sample is loaded ontoNuPage 4-12% Bis-Tris gels (Invitrogen, NP0323). Proteins aretransferred to nitrocellulose membranes (Invitrogen, LC2001), blockedfor 1 h in Odyssey Blocking Buffer (Li-Cor, 927-40000), and incubated at4° C. overnight with the following antibodies diluted in OdysseyBlocking Buffer: Anti-phospho-AKT^(T308) (1:200, Cell SignalingTechnology, 2965), Anti-phospho-AKT^(S473) (1:200, Cell SignalingTechnology, 4060), Anti-AKT (1:1,000, R&D Systems, MAB 2055), andAnti-GAPDH (1:100,000, Advanced Immunochemical Inc, MAB6C5). Membranesare washed four times for 10 min each with TBS-T buffer (50 mM Tris-HCl,pH 7.2; 150 mM NaCl; 0.1% Tween-20) and blotted with Goatanti-Mouse-IRDye680 (Li-Cor, 926-32220) and Goat anti-Rabbit-IRDye800(Li-Cor, 926-32211) secondary antibodies in Odyssey Blocking buffercontaining 0.1% Tween-20 for 60 mM at room temperature. Membranes arewashed four times for 10 min each with TBS-T buffer and rinsed with PBStwice. The membranes are scanned using the Odyssey Scanner (Li-Cor) andthe signal intensity of each band is quantified using ImageQuant(Molecular Devices). IC₅₀ values are calculated based on the signal withcompound treatment compared to the vehicle (DMSO) control.

Anti-IgM-Stimulated Raji Cell TNF-Alpha Cytokine Release Assay

Raji cells (ATCC, CCL-86) are seeded at 2×10⁵ cells/well in 96-well cellculture cluster round-bottom plates (Corning, Costar 3790) in RPMI 1640medium (ATCC, 30-2001) containing 10% FBS (Heat-Inactivated, Gibco,10082) with 1% Penicillin/Streptomycin (Cellgro, 30-002-CI). Cells aretreated with serially diluted compounds for 2 h at 37° C. in 5% CO₂.Cells are stimulated with 1 μg/mL anti-IgM antibody (Southern Biotech,9023-01) for 4 h. Minimal signal wells are treated with commerciallyavailable PI-103 (CAS 371935-74-9) and maximal signal wells are in 0.3%DMSO, both stimulated with anti-IgM. Unstimulated cells are alsoincluded as a negative control. After treatment, culture supernatantsare filtered using 96-well 0.2-μm PVDF filter plates (Corning, Costar3504). Filtered conditioned medium is added to MSD plates (K151BHB-2)and incubated for 3 h at room temperature with agitation on a shaker(600 rpm). Plates are washed three times with phosphate-buffered saline(PBS; 137 mM NaCl, 2.7 mM KCl, 6.5 mM Na₂HPO₄, 1.7 mM KH₂PO₄) containing0.05% Tween-20 (Bio-Rad, 161-0781). Detection Antibody Solution (MesoScale Discovery, K151BHB-2) is added to each well and incubated for 2 hat room temperature. Plates are then washed three times withphosphate-buffered saline (PBS; 137 mM NaCl, 2.7 mM KCI, 6.5 mM Na₂HPO₄,1.7 mM KH₂PO₄) containing 0.05% Tween-20 (Bio-Rad, 161-0781). ReadBuffer T (Meso Scale Discovery, K151BHB-2) is added to each well, andthen the plates are analyzed on the MSD SECTOR Imager. IC₅₀ values arecalculated based on the signal of cells with compound treatment comparedto those of the corresponding maximal and minimal signal wells.

Anti-IgM-Stimulated Human Peripheral Blood B-Lymphocytes CytokineRelease Assay

Human primary peripheral blood B cells (Negatively selected, CD19⁺,AllCells, PB010) are seeded at 1×10⁵ cells/well onto 96-well microtitercluster plates (Costar, 3790) in RPMI 1640 medium (ATCC, 30-2001)containing 10% FBS (Heat Inactivated, Gibco, 10082), 1%Penicillin/Streptomycin (Cellgro, 30-002-CI), 1% L-glutamine (Cellgro,25-015-CI), and 50 μM P-mercaptoethanol (Gibco, 21985-0233). Serialdilutions of compound in a final concentration of 0.3% DMSO (vehicle)are added to the cells and incubated at 37° C., 5% CO₂ for 2 h.Duplicate wells are used for each compound concentration. Minimum signalwells received 30 μM PI-103, a pan-PI3K inhibitor. Cells in all wellsare then stimulated with anti-IgM (Jackson Immunoresearch, 109-006-129)for an additional 4 h at 37° C., 5% CO₂. Cells are then transferred onto96-well filter plates (Corning Costar, 3504), and supernatants collectedby vacuum filtration. The supernatants are frozen at −80° C. until timeof assay. According to the manufacturer's instructions, supernatants areassayed for cytokine levels using the Human Pro-inflammatory 9-PlexTissue Culture Kit (GM-CSF, IFN-gamma, IL-10, IL-12 p70, IL-2, IL-6,IL-8, TNF-alpha; Meso Scale Discovery, K15007B-1). Briefly, supernatantsare added onto pre-blocked assay plates and incubated at roomtemperature for 2 h with vigorous shaking at 600 rpm. Detectionantibodies are then added onto the supernatants and incubated at roomtemperature for an additional 2 h with vigorous shaking at 600 rpm.Plates are washed three times with phosphate-buffered saline (PBS; 137mM NaCl, 2.7 mM KCl, 6.5 mM Na₂HPO₄, 1.7 mM KH₂PO4) containing 0.05%Tween-20 (Bio-Rad, 161-0781) and electrochemiluminescence detected usingthe MSD SI2400 plate reader. IC₅₀ values are calculated based on thecalculated cytokine concentration with compound treatment minus theminimum signal compared to the DMSO vehicle control.

CpG ODN-Stimulated Human Peripheral Blood B-lymphocytes Cytokine ReleaseAssay

Human primary peripheral blood B-cells (Negatively selected, CD 19⁺,AllCells, PB010) are seeded at 1×10⁵ cells/well onto 96-well microtitercluster plates (Corning, Costar 3790) in RPMI 1640 medium (ATCC,30-2001) containing 10% FBS (Heat Inactivated, Gibco, 10082), 1%Penicillin/Streptomycin (Cellgro, 30-002-CI), 1% L-glutamine (Cellgro,25-015-CI), and 50 μM beta-mercaptoethanol (Gibco, 21985-023). Serialdilutions of compound in a final concentration of 0.3% DMSO (vehicle)are added to the cells and incubated at 37° C., 5% CO2 for 2 h.Duplicate wells are used for each compound concentration. Minimum signalwells received 30 μM commercially available PI-103 (CAS 371935-74-9), apan-PI3K inhibitor. Cells in all wells are then stimulated with CpG ODN(Imgenex, IMG-2209H) for an additional 4 h at 37° C., 5% CO₂. Cells arethen transferred onto 96-well filter plates (Corning, Costar 3504), andsupernatants collected by vacuum filtration. The supernatants are frozenat −80° C. until time of assay. According to the manufacturer'sinstructions, supernatants are assayed for cytokine levels using theHuman Pro-inflammatory 9-Plex Tissue Culture Kit (GM-CSF, IFN-gamma,IL-1 beta, IL-10, IL-12 p70, IL-2, IL-6, IL-8, TNF-alpha; Meso ScaleDiscovery, K15007B-1). Briefly, supernatants are added onto pre-blockedassay plates and incubated at room temperature for 2 h with vigorousshaking at 600 rpm. Detection antibodies are then added onto thesupernatants and incubated at room temperature for an additional 2 hwith vigorous shaking at 600 rpm. Plates are washed three times withphosphate-buffered saline (PBS; 137 mM NaCl, 2.7 mM KCl, 6.5 mM Na₂HPO₄,1.7 mM KH₂PO4) containing 0.05% Tween-20 (Bio-Rad, 161-0781) andelectrochemiluminescence detected using the MSD SI2400 plate reader.IC₅₀ values are calculated based on the calculated cytokineconcentration with compound treatment minus the minimum signal comparedto the DMSO vehicle control.

Anti-CD3-mediated Human Peripheral Blood T-Lymphocytes Cytokine ReleaseAssay

Human peripheral blood mononuclear cells (PBMCs) from healthy humandonors are isolated using a sodium diatrizoate polysucrose gradient(Accuspin System Histopaque-1077, Sigma-Aldrich, A7054). Cells are thennegatively selected according to manufacturer's instructions using theEasySep Human T cell Enrichment kit (Stem Cell Technologies, 19051).Cells are more than 95% pure. CD3⁺ T cells are seeded at 1×10⁵cells/well onto 96-well microtiter cluster plates (Corning, Costar 3790)in RPMI 1640 medium (ATCC, 30-2001) containing 10% FBS (HeatInactivated, Gibco, 10082), 1% Penicillin/Streptomycin (Cellgro,30-002-CI), 1% L-glutamine (Cellgro, 25-015-CI), and 50 μMbeta-ercaptoethanol (Gibco, 21985-023). Serial dilutions of compound ina final concentration of 0.3% DMSO (vehicle) are added to the cells andincubated at 37° C., 5% CO₂ for 2 h. Duplicate wells are used for eachcompound concentration. Minimum signal wells received 30 μM commerciallyavailable PI-103 (CAS 371935-74-9), a pan-PI3K inhibitor. Cells in allwells are then seeded onto anti-human CD3-coated 96-well microtiterplates (BD Biosciences, 354725) for an additional 4 h at 37° C., 5% CO₂.Cells are then transferred onto 96-well filter plates (Corning, Costar3504), and supernatants collected by vacuum filtration. The supernatantsare frozen at −80° C. until time of assay. According to themanufacturer's instructions, supernatants are assayed for cytokinelevels using the Human TH1/TH2 10-Plea Tissue Culture Kit (IFN-gamma,IL-1 beta, IL-10, IL-12 p70, IL-13, IL-2, IL-4, IL-5, IL-8, TNF-alpha;Meso Scale Discovery, K15010B-1). Briefly, supernatants are added ontopre-blocked assay plates and incubated at room temperature for 2 h withvigorous shaking at 600 rpm. Detection antibodies are then added ontothe supernatants and incubated at room temperature for an additional 2 hwith vigorous shaking at 600 rpm. Plates are washed three times withphosphate-buffered saline (PBS; 137 mM NaCl, 2.7 mM KCl, 6.5 mM Na₂HPO₄.1.7 mM KH₂PO₄) containing 0.05% Tween-20 (Bio-Rad, 161-0781) andelectrochemiluminescence detected using the MSD SI2400 plate reader.IC₅₀ values are calculated based on the calculated cytokineconcentration with compound treatment minus the minimum signal comparedto the DMSO vehicle control.

LPS-stimulated Peripheral Blood Mononuclear Cell Cytokine Release Assay

Human primary peripheral blood mononuclear cells (PBMC, AllCells, PB001)are seeded at 2×10⁵ cells/well onto 96-well microtiter cluster plates(Coming. Costar 3790) in RPMI 1640 medium (ATCC, 30-2001) containing 10%FBS (Heat Inactivated, Gibco, 10082), 1% Penicillin/Streptomycin(Cellgro, 30-002-CI), 1% L-glutamine (Cellgro, 25-015-CI), and 50 μM13-mercaptoethanol (Gibco, 21985-023). Serial dilutions of compound in afinal concentration of 0.3% DMSO (vehicle) are added to the cells andincubated at 37° C., 5% CO₂ for 2 h. Duplicate wells are used for eachcompound concentration. Minimum signal wells received 30 μM commerciallyavailable PI-103 (CAS 371935-74-9), a pan-PI3K inhibitor. Cells in allwells are then stimulated with lipopolysaccharide (LPS, Sigma, L4391)for an additional 6 h at 37° C., 5% CO₂. Cells are then transferred onto96-well filter plates (Corning, Costar 3504), and supernatants collectedby vacuum filtration. The supernatants are frozen at −80° C. until timeof assay. According to the manufacturer's instructions, supernatants areassayed for cytokine levels using the Human Pro-inflammatory 9-PlexTissue Culture Kit (GM-CSF, IFN-gamma, IL-(beta, IL-10, IL-12 p70, IL-2,IL-6, IL-8, TNF-alpha; Meso Scale Discovery, K15007B-1). Briefly,supernatants, either undiluted or diluted 1:2, are added ontopre-blocked assay plates and incubated at room temperature for 2 hourswith vigorous shaking at 600 rpm. Detection antibodies are then addedonto the supernatants and incubated at room temperature for anadditional 2 h with vigorous shaking at 600 rpm. Plates are washed threetimes with phosphate-buffered saline (PBS; 137 mM NaCl, 2.7 mM KCl, 6.5mM Na₂HPO₄, 1.7 mM KH₂PO₄) containing 0.05% Tween-20 (Bio-Rad, 161-0781)and electmchemiluminescence detected using the MSD SI2400 plate reader.IC₅₀ values are calculated based on the calculated cytokineconcentration with compound treatment minus the minimum signal comparedto the DMSO vehicle control.

Primary Human B- and T-lymphocyte BrdU Proliferation Assay

Human primary B-lymphocytes (B cells, AllCells, PB010) are seeded at1×10⁵ cells/well onto 96-well microtiter cluster plates (Corning, Costar3790) and human primary T-lymphocytes (T cells, AllCells, PB009-1) areseeded at 2×10⁵ cells/well onto anti-human CD3-coated 96-well microtiterplates (BD Biosciences, 354725) in RPMI-1640 medium (ATCC, 30-2001)containing 10% FBS (Heat Inactivated, Gibco, 10082), 1%Penicillin/Streptomycin (Cellgro, 30-002-CI), 1% L-glutamine (Cellgro,25-015-CI), and 50 μM beta-mercaptoethanol (Gibco, 21985-023). The humanprimary B cells are stimulated with either anti-human IgM (JacksonImmunoresearch, 109-006-129) at a final concentration of 25 μg/mL orwith CpG ODN (Imgenex, IMG-2209H) at a final concentration of 2 μg/mL.Both B and T cells are treated immediately after stimulation with aserial dilution of compound in medium (containing a final concentrationof 0.3% DMSO). Triplicate wells are used for each compound concentrationin B cells, and duplicate wells are used for each compound concentrationin T cells. The control wells received 0.3% DMSO media. The minimumsignal wells received 30 μM of commercially available PI-103 (CAS371935-74-9), a pan-PI3K inhibitor. The cultures are incubated at 37°C., 5% CO₂ for 72 h (B cells) or 96 h (T cells). To assay the cells,they are labeled with 20 μM bromodeoxyuridine (BrdU, Sigma,B5002-500MG), transferred to 96-well filter plates (Costar 3504), andthen fixed with FixDenat solution (70% ethanol+0.1M NaOH). Anti-BrdU-POD(1:2,000; Roche, 11585860001) conjugate is added to the cells, afterwhich the plates are washed 3 times with phosphate-buffered saline (PBS;137 mM NaCl, 2.7 mM KCl, 6.5 mM Na₂HPO₄, 1.7 mM KH₂PO₄). Substratesolution made from 1 part peroxide (Thermo Scientific, 37075A) and 1part luminol (Thermo Scientific, 37075B) is added, and the plates areread for luminescence (0.1 s) using the Victor Wallac luminometer. IC₅₀values are calculated based on the cell proliferation with compoundtreatment minus the minimum signal compared to the DMSO vehicle control.

MC/9 Mouse Mast Cell β-Hexosaminidase Degranulation Assay

MC/9 cells (ATCC, CRL-8306) are seeded at 1×10⁶ cells/mL ontotissue-culture flasks (Nunc, 144903) in DMEM (Cellgro, 10-013-CV)containing 10% FBS (Heat-Inactivated, Gibco, 10082), 1.5 g/L sodiumbicarbonate, 0.05 mM 2-mercaptoethanol, 10% Rat T-STIM (BD, 354115), and1% Penicillin/Streptomycin (Cellgro, 30-002-CI). Cells are incubatedwith 200 ng/mL anti-DNP IgE (Sigma, D8406) overnight at 37° C. in 5%CO₂. Cells are washed twice with Tyrode's buffer (135 mM NaCl , 5 mMKCl, 5.6 mM glucose, 1.8 mM CaCl₂. 1 mM MgCl₂, 20 mM HEPES, and 0.5mg/mL BSA; pH 7.3) and seeded at 2×10⁵ cells/well in 96-well microtiterplates (Costar, 3904) in 70 μL of Tyrode's buffer. 30 μL of seriallydiluted test compounds in Tyrode's buffer with a final concentration of0.3% DMSO (vehicle) are added to the cells and incubated for 75 min.Cells are stimulated with 200 ng/mL DNP-HSA (Sigma, A6661) for 45 min.Background wells are cells in 0.3% DMSO without DNP-HSA stimulation.Minimal signal wells are treated with commercially available PI-103 (CAS371935-74-9), 10 μM) and maximal signal wells are in 0.3% DMSO, bothstimulated with DNP-HSA. The final volume per well is 110 μL. Afterstimulation, cells are spun down at 400×g for 4 min. 50 μL ofsupernatant is carefully collected and transferred to a 96-well plate(Nunc, 260895) and incubated with 75 μL. of 1 mM p-nitrophenylacetyl-D-glucosamine (Sigma, N9376) in citrate buffer (pH 4.5) for 2 hat 37° C. The reaction is stopped by adding 75 μL of 2 M NaOH. Wells aremeasured for absorbance at wavelength of 405 nm with correction at 630nm using a spectrophotometer (Molecular Devices, SpectraMax Plus). Theaverage background well values are subtracted from all wells. IC₅₀values are calculated based on the absorbance of cells with compoundtreatment compared to those of the corresponding maximal and minimalsignal wells.

Example 3 Pharmacodynamic Xenograft Tumor Models

Female and male athymic nude mice (NCr) 5-8 weeks of age and weighingapproximately 20-25 g are used in the following models. Prior toinitiation of a study, the animals are allowed to acclimate for aminimum of 48 h. During these studies, animals are provided food andwater ad libitum and housed in a room conditioned at 70-75° F. and 60%relative humidity. A 12 h light and 12 h dark cycle is maintained withautomatic timers. All animals are examined daily for compound-induced ortumor-related deaths.

Tumor weight (TW) in the above models is determined by measuringperpendicular diameters with a caliper, using the following formula:

Tumor Weight (mg)=[tumor volume=length (mm)×width² (mm²)]/2

These data are recorded and plotted on a tumor weight vs. dayspost-implantation line graph and presented graphically as an indicationof tumor growth rates. Percent inhibition of tumor growth (TGI) isdetermined with the following formula:

$\left\lbrack {1 - \left( \frac{\left( {X_{f} - X_{0}} \right)}{\left( {Y_{f} - X_{0}} \right)} \right)} \right\rbrack*100$

where:

X₀=average TW of all tumors on group day

X_(f)=TW of treated group on Day f

Y_(f)=TW of vehicle control group on Day f

If tumors regress below their starting sizes, then the percent tumorregression is determined with the following formula:

$\left( \frac{X_{0} - X_{f}}{X_{0}} \right)*100$

Tumor size is calculated individually for each tumor to obtain amean±SEM value for each experimental group. Statistical significance isdetermined using the 2-tailed Student's t-test (significance defined asP<0.05).

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Theinvention has been described with reference to various specificembodiments and techniques. However, it should be understood that manyvariations and modifications may be made while remaining within thespirit and scope of the invention. It will be obvious to one of skill inthe art that changes and modifications may be practiced within the scopeof the appended claims. Therefore, it is to be understood that the abovedescription is intended to be illustrative and not restrictive. Thescope of the invention should, therefore, be determined not withreference to the above description, but should instead be determinedwith reference to the following appended claims, along with the fullscope of equivalents to which such claims are entitled. All patents,patent applications and publications cited in this application arehereby incorporated by reference in their entirety for all purposes tothe same extent as if each individual patent, patent application orpublication were so individually denoted.

What is claimed is:
 1. A compound of Formula I

or a stereoisomer or mixture of stereoisomers thereof, optionally as apharmaceutically acceptable salt thereof, wherein: A is N, C—H, or C—OH;B is C—H or N; E is absent or is C—R⁴; G is S C—H, or C—R³; J is C or Nwhen A is C—H or C—OH, or J is C when A is N; X is absent or is NH or isoptionally substituted N—(C₁-C₆)alkyl; Y is absent or is optionallysubstituted (C₁-C₆)alkylene wherein up to two carbon atoms of the(C₁-C₆)alkylene are replaced by O, NH, N—(C₁-C₆)alkyl, —NH—(C═O)—,—N(C₁-C₆)alkyl—(C═O)—, or —(C═O)—; Q is absent or is (C₁-C₆)alkylene; Zis absent or is NH, N(C₁-C₆)alkyl, NH(C₁-C₆)alkylene, —NH—(C═O)—,—N(C₁-C₆)alkyl—(C═O)—, S, SO, SO₂, or O; R¹ is halo, hydroxy, cyano,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocycloalkyl, optionally substituted(C₁-C₆)alkyl, optionally substituted (C₁-C₆)alkoxy, (C₁-C₆)alkyl—OH,NH₂, —NH—(C₁-C₆)alkyl, —NH—((C₁-C₆)alkyl)₂, —NH—(C═O)—R⁵, —(C═O)NR⁶R⁷,or —NH—(SO₂)—R⁸; R² is NH₂, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, or optionally substitutedheteroaryl, ‘R³ at each occurrence is independently halo, cyano,optionally substituted (C₁-C₆)alkyl, or (C₁-C₆)alkoxy; R⁴ is H oroptionally substituted (C₁-C₆)alkyl; R⁵ is H, optionally substituted(C₁-C₆)alkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl; R⁶ and R⁷ are each independently H, optionally substituted(C₁-C₆)alkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, or R⁶ and R⁷, together with the atoms to which they areattached, can be taken together to form an optionally substituted 3, 4,5, 6, or 7-membered ring; R⁸ is optionally substituted (C₁-C₆)alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl.
 2. The compound of claim 1, which is a compound of FormulaI-a or I-b.


3. The compound of claims 1-2, which is a compound of Formula I-c.


4. The compound of claims 1-3, which is a compound of Formula I-d.


5. The compound of claims 1-4, which is a compound of I-e.


6. The compound of claims 1-5, wherein R⁴ is H or methyl.
 7. Thecompound of claim 6, wherein Q is absent or is (C₁-C₄)alkylene and Z isabsent or is NH, N(C₁-C₆)alkyl, —NH—(C═O)—, —N(C₁-C₆)alkyl—(C═O)—, O, orS.
 8. The compound of claim 7, which is a compound of Formula I-f orI-g, wherein R⁹ is H or CH₃.


9. The compound of Formula I-g of claim 8, wherein Y is optionallysubstituted (C₁-C₆)alkylene, wherein up to two carbon atoms of the(C₁-C₆)alkylene are replaced by NH, N(C₁-C₆)alkyl, —NH—(C═O)—,—N(C₁-C₆)alkyl—(C═O)—, or (C═O)—.
 10. The compound of claims 8-9,wherein Q is CH₂ or CH(CH₃).
 11. The compound of claim 10, wherein Z isabsent or is —NH—, —NH—(C═O)—, or S.
 12. The compound of claims 1-11,wherein R¹ is halo, —OH, —NH₂, or cyano, or is (C₁-C₆)alkyl,(C₁-C₆)alkoxy, pyrrolidinyl, piperidinyl, piperizinyl,octahydro-pyridopyrazinyl, pyrazolyl, triazolyl, tetrazolyl, phenyl,pyridyl, imidazolyl, diazepinyl, morpholinyl, —SO₂—(C₁-C₆)alkyl,—SO₂—aryl, —NH—(C₁-C₆)alkyl, —NH—((C₁-C₆)alkyl)₂,octahydroisoquinolinyl, dihydroisoquinolinyl, benzimidazolyl, furanyl,pyrazinyl, thiazolyl, diazabicyclo[2.2.1]hept-2-yl, pyranyl,tetrahydropyranyl, any of which may be optionally substituted.
 13. Thecompound of claim 12, wherein R¹ is bromo, —OH, —NM, cyano, —CH₃, —OCH₃,SO₂—CH₃,


14. The compound of claim 13, wherein R² is NH₂, purinyl, pyrazinyl,pyrazolopyrimidinyl, benzodioxinyl, phenyl, morpholinyl, oxadiazolyl,cyclopropyl, or pyridinyl, any of which may be optionally substituted.


15. The compound of claim 14, wherein R² is NH₂,
 16. The compound ofclaims 1-15, which is a compound of Formula II.


17. The compound of claim 16, which is a compound of Formula II-a, II-b,II-c, or II-d.


18. The compound of claim 17, wherein Z is absent or is O, S, —NH— or—NH(C═O)—
 19. A compound of claims 1-18 which is:9-{[2-(2-methylphenyl)quinolin-3-yl]methyl}-9H-purin-6-amine;9-{[3-(2-methylphenyl)quinoxalin-2-yl]methyl}-9H-purin-6-amine;9-{[8-methyl-2-(2-methylphenyl)quinolin-3-yl]methyl}-9H-purin-6-amine;8-methyl-2-(2-methylphenyl)-3-[(9H-purin-6-ylthio)methyl]quinoline;9-{[2-(2-chlorophenyl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine;9-({2-[2-(ethyloxy)phenyl]-8-methylquinolin-3-yl}methyl)-9H-purin-6-amine;9-({8-methyl-2-[3-(methyloxy)phenyl]quinolin-3-yl}methyl)-9H-purin-6-amine;9-{[8-methyl-2-(3-{[2-(methyloxy)ethyl]oxy}phenyl)quinolin-3-yl]methyl}-9H-purin-6-amine;9-{[8-methyl-2-(3-methylphenyl)quiriolin-3-yl]methyl}-9H-purin-6-amine;9-({8-methyl-2-[2-(trifluoromethyl)phenyl]quinolin-3-yl}methyl)-9H-purin-6-amine;9-{[2-(2,5-dimethylphenyl)-8-methylquinolin-3-yl[methyl}-9H-purin-6-amine;9-{[2-(2,3-dimethylphenyl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine;9-{[3-(2-methylphenyl)quinolin-2-yl]methyl}-9H-purin-6-amine;7-{[3-(2-methylphenyl)quinolin-2-yl]methyl}-7H-purin-6-amine;9-[(8-methyl-2-morpholin-4-ylquinolin-3-yl)methyl]-9H-purin-6-amine;2-amino-N-{[5-methyl-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl)pyridine-3-carboxamide;3-amino-N-{[5-methyl-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl}pyrazine-2-carboxamide;2-amino-N-{[5-methyl-3-(2-methylphenyI)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl}pyridine-4-carboxamide;9-{[8-methyl-2-(4-methylpiperazin-1-yl)quinolin-3-yl]methyl}-9H-purin-6-amine;9-[(8-methyl-2-p iperazin-1-ylquinolin-3-yl)methyl]-9H-purin-6-am ine;9-[(8-methyl-2-pyrroidin-1-ylquinolin-3-yl)methyl]-9H-purin-6-amine;9-{[8-methyl-2-(2-methylpyrrolidin-1-yl)quiriolin-3-yl]methyl}-9H-purin-6-amine;7-{[4-methyl-3-(2-methylphenyl)quinolin-2-yl]methyl}-7H-purin-6-amine;9-{[4-methyl-3-(2-methylphenyl)quinolin-2-yl]methyl}-9H-purin-6-amine;3-[(6-amino-9H-purin-9-yl)methyl]-8-methyl-N-[2-(methyloxy)ethyl]quinolin-2-amine;9-{[2-(4-acetylpiperazin-1-yl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine;3-[(6-amino-9H-purin-9-yl)methyl]-8-methyl-N-(tetrahydro-2H-pyran-4-yl)quinolin-2-amine;3-[(6-amino-9H-purin-9-yl)methyl]-8-methyl-N-(1-methylpiperidin-4-yl)quinolin-2-amine;3-(2-methylphenyl)-2-[(7H-purin-6-ylthio)methyl]thieno[3,2-d]pyrimidin-4(3H)-one;2-[(6-amino-9H-purin-9-yl)methyl]-3-(2-methylphenyl)thieno[3,2-d]pyrimidin-4(3H)-one;3-amino-N-{[5-methyl-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl}pyridine-2-carboxamide;3-amino-6-bromo-N-{[5-methyl-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl}pyrazine-2-carboxamide;3-chloro-N-{[5-methyl-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl}pyrazine-2-carboxamide;3-({[3,5-bis(methyloxy)phenyl]methyl}oxy)-8-methyl-2-(2-methylphenyl)quinolhie;2-(2-aminoethyl)-5-methyl-3-(2-methylphenyl)quinazolin-4(3H)-one;N-{3-[(6-amino-9H-purin-9-yl)methyl]-8-methylquinolin-2-yl}benzenesulfonamide;N-{[3-(2-methylphenyl)quinolin-2-yl]methyl}-9H-purin-6-amine;N-{[2-(2-chlorophenyl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine;N-{3-[(6-amino-9H-purin-9-yl)methyl]-8-methylquinolin-2-yl}methanesulfonamide;N-{1-[2-(2-chlorophenyl)-8-methylquinolin-3-yl]ethyl}-9H-purin-6-amine;N-{[5-methyl-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl}-3-morpholin-4-ylpyrazine-2-carboxamide;9-{[8-methyl-2-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)quinolin-3-yl]methyl}-9H-purin-6-amine;N-{3-[(6-amino-9H-purin-9-yl)methyl]-8-methylquinolin-2-yl}-N,N′-dimethylethane-1,2-diamine;3-amino-N-{[2-(2-chlorophenyl)-8-methylquinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-[(8-methyl-2-piperidin-1-ylquinolin-3-yl)methyl]pyrazine-2-carboxamide;N-{(8-methyl-2-(4-methyl-1,4-diazepan-1-yl)quinolin-3-yl]methyl}-9H-purin-6-amine;3-iodo-1-{[3-(2-methylphenyl)quinolin-2-yl]methyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine;N-{[2-(4-ethylpiperazin-1-yl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine;N-{[2-(4-acetylpiperazin-1-yl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine;3-amino-N-{[3-(2-methylphenyl)quinolin-2-yl]methyl}pyrazine-2-carboxamide;3-bromo-N-{[3-(2-methylphenyl)quinolin-2-yl]methyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine;3-amino-N-{[8-methyl-2-(4-methyl-1,4-diazepan-1-yl)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-{[2-(1,4-diazepan-1-yl)-8-methylquinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-[(2-{[3-(dimethylamino)propyl]amino}-8-methylquinolin-3-yl)methyl]pyrazine-2-carboxamide;3-amino-N-({2-[4-(N,N-dimethylglycyl)-1,4-diazepan-1-yl]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({2-[{3-[(N,N-dimethylglycyl)(methyl)amino]propyl}(methyl)amino]-8-methylquinolin-3-yl)methyl}pyrazine-2-carboxamide;3-iodo-N-{[8-methyl-2-(2-methyl phenyl)quinolin-3-yl]methyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine;3-iodo-1-{[8-methyl-2-(2-methylphenyl)quinolin-3-yl]methyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine;3-amino-N-[(8-methyl-2-{methyl[3-(methylamino)propyl]amino}quinolin-3-yl)methyl]pyrazine-2-carboxamide; N˜5˜-{[3-(2-methylphenyl)quinolin-2-yl]methyl}pyrimidine-4,5-diamine;3-amino-N-[(8-methyl-2-piperazin-1-ylquinolin-3-yl)methyl]pyrazine-2-carboxamide;3-amino-N-[(8-methyl-2-{methyl[2-(methylamino)ethyl]amino}quinolin-3-yl)methyl]pyrazine-2-carboxamide;3-amino-N-[(2-{[2-(dimethylamino)ethyl]amino}-8-methylquinolin-3-yl)methy]pyrazine-2-carboxamide;3-amino-N-[(2-{[2-(dimethylamino)ethyl](methyl)amino{-8-methylquinolin-3-yl)methyl]pyrazine-2-carboxamide;3-amino-N-({2-[4-(dimethylamino)piperidin-1-yl]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide;1,1-dimethylethyl{1-[3-({[(3-aminopyrazin-2-yl)carbonyl]amino}methyl)-8-methylquinolin-2-yl]piperidin-4-yl}methylcarbamate;3-amino-N-({2-[(2-hydroxyethyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide;N-{[2-(4-acetylpiperazin-1-yl)-8-methylquinolin-3-yl]methyl}-3-aminopyrazine-2-carboxamide;3-amino-N-({2-[(2R,5S)-2,5-dimethylpiperazin-1-yl]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-[(8-methyl-2-{[2-(methylamino)ethyl]oxy}quinolin-3-yl)methyl]pyrazine-2-carboxamide;3-amino-N-({2-[(2-hydroxyethyl)(methyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide;9-{[3-(2-methylphenyl)naphthalen-2-yl]methyl}-9H-purin-6-amine;3-iodo-1-{[5-methyl-3-(2-methylphenyl)quinolin-2-yl]methyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine;3-amino-N-{[5-methyl-3-(2-methylphenyl)quinolin-2-yl]methyl}pyrazine-2-carboxamide;3-iodo-1-{1-[3-(2-methylphenyl)quinolin-2-yl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine;3-amino-N-{[8-methyl-2-(methyl{2-[methyl(N-methylglycyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-({2-[{2-[glycyl(methyl)amino]ethyl}(methyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({2-[{(2-[(N,N-dimethylglycyl)(methyl)amino]ethyl}(methyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-(methyl(1-methyl-L-prolyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-{(2-(1H-benzimidazol-1-yl)-8-methylquinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-{[2-(1H-imidazol-1-yl)-8-methylquinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-({8-methyl-2-[methyl(2-{methyl[(1-methyl-1H-imidazol-5-yl)carbonyl]amino}ethyl)amino}quinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-[methyl(pyrrolidin-1-ylacetyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;4-amino-N-{[3-(2-methylphenyl)quinolin-2-yl]methyl}pyrimidine-5-carboxamide;3-amino-5-chloro-N-{[3-(2-methylphenyl)quinolin-2-yl]methyl}pyrazine-2-carboxamide;3-amino-5-(methyloxy)-N-{[3-(2-methylphenyl)quinolin-2-yl]methyl}pyrazine-2-carboxamide;3-amino-N-{[3-(2-methylphenyl)quinolin-2-yl]methyl}-5-morpholin-4-ylpyrazine-2-carboxamide;3-amino-N-[(8-methyl-2-{methyl[2-(methyloxy)ethyl]amino}quinolin-3-yl)methyl]pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-[methyl(L-prolypamino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-[methyl(D-prolyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-[methyl(methylsulfonyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-[methyl(1H-1,2,3-triazol-1-ylacetyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-({8-methyl-2-[methyl(1-methylpiperidin-4-yl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({8-methyl-2-[methyl(1-methylpyrrolidin-3-yl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({8-methyl-2-[(2-pyridin-3-ylethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({8-methyl-2-[(2-pyridin-2-ylethyl)amino]quinolin-3-yl}methyl)pymzine-2-carboxamide;3-amino-N-({8-methyl-2-[(pyridin-3-ylmethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-[methyl(2H-1,2,3-triazol-2-ylacetyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-[(3-bromoquinolin-2-yl)methyl]pyrazine-2-carboxamide;3-amino-N-{(3-{2-{(dimethylamino)methyl]phenyl}quinolin-2-yl)methyl]pyrazine-2-carboxamide;3-amino-N-{[3-(1,3-thiazol-4-yl)quinolin-2-yl]methyl}pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-[methyl(pyrazin-2-yl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-({2-[(2-{[2-(dimethylamino)-2-oxoethyl](methyl)amino}ethyl)(methyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({8-methyl-2-[methyl(2-pyridin-2-ylethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({8-methyl-2-[methyl(pyridin-3-ylmethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({8-methyl-2-[methyl(2-{methyl[(2-methyl-1H-imidazol-1-yl)acetyl]amino}ethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({2-[{2-[(1H-imidazol-1-ylacetyl)(methyl)amino]ethyl}(methyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({2-{[2-[(cyanomethyl)(methyl)amino]ethyl}(methyl)amino]-8-methylquinolin-3-yl}methyppyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-[methyl(pyridin-3-ylmethyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-({8-methyl-2-[methyl(2-{methyl[(4-methylphenyl)sulfonyl]amino}ethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl[2-[methyl(pyridin-2-ylcarbonyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-[methyl(pyridin-3-ylcarbonyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-[methyl(pyridin-4-ylcarbonyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-[methyl(pyrazin-2-ylarbonyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-[methyl(2-morpholin-4-yl-2-oxoethyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-({8-methyl-2-[methyl(2-{methyl[2-(methylamino)-2-oxoethyl]amino}ethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-{1-[3-(2-methylphenyl)quinolin-2-yl]ethyl}pyrazine-2-carboxamide;2-amino-N-{[3-(2-methylphenyl)quinolin-2-yl]methyl}pyrimidine-5-carboxamide;3-amino-N-({8-methyl-2-[methyl(2-{methyl[1-(1-methylethyl)-D-prolyl]amino}ethyl)amino]quinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({3-[3-(morpholin-4-ylmethyl)phenyl]quinolin-2-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({3-[4-(morpholin-4-ylmethyl)phenyl]quinolin-2-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({3-[2-(morpholin-4-ylmethyl)phenyl]quinolin-2-yl}methyl)pyrazine-2-carboxamide;3-amino-N-[(3-{3-[(dimethylamino)methyl]phenyl}quinolin-2-yl}methyl)pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl[2-[methyl(pyridin-2-ylmethyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-[methyl(1-propyl-D-proly)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-[(2-{4-[2-(dimethylamino)-2-oxoethyl]-1,4-diazepan-1-yl}-8-methylquinolin-3-yl)methyl]pyrazine-2-carboxamide;3-amino-N-({8-methyl-2-[4-(pyridin-4-ylmethyl)-1,4-diazepan-1-yl]quinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({8-methyl-2-[4-(pyridin-3-ylmethyl)-1,4-diazepan-1-yl]quinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-[(8-methyl-2-{4-[(1-methyl-1H-imidazol-5-yl)methyl]-1,4-diazepan-1-yl}quinolin-3-yl)methyl]pyrazine-2-carboxamide;3-amino-N-[(8-methyl-2-{4-[(1-methyl-1H-imidazol-2-yl)methyl]-1,4-diazepan-1-yl}quinolin-3-yl)methyl]pyrazine-2-carboxamide;3-amino-N-({8-methyl-2-[4-(2H-1,2,3-triazol-2-ylacetyl)-1,4-diazepan-1-yl]quinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({8-methyl-2-[4-(1H-1,2,3-triazol-1-ylacetyl)-1,4-diazepan-1-yl]quinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({3-[2-(piperidin-1-ylmethyl)phenyl]quinolin-2-yl}methyl)pyrazine-2-carboxamide;3-amino-N-[(8-methyl-2-{4-[(5-methylfuran-2-yl)methyl]-1,4-diazepan-1-yl}quinolin-3-yl)methyl]pyrazine-2-carboxamide;3-amino-N-[(8-methyl-2-{4-[(1-methyl-1H-pyrrol-2-yl)methyl]-1,4-diazepan-1-yl}quinolin-3-yl)methyl]pyrazine-2-carboxamide;3-amino-N-[(3-{2-[(dimethylamino)carbonyl]phenyl}quinolin-2-yl)methyl]pyrazine-2-carboxamide;3-amino-N-[(8-methyl-2-{4-[(2-methyl-1H-imidazol-1-yl)acetyl]-1,4-diazepan-1-yl}quinolin-3-yl)methyl]pyrazine-2-carboxamide;3-amino-N-({2-[4-(1H-imidazol-1-ylacetyl)-1,4-diazepan-1-yl]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({2-[4-(1H-benzimidazol-1-ylacetyl)-1,4-diazepan-1-yl[-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-[(3-[(2-[(dimethylamino)methyl]phenyl}-5-methylquinolin-2-yl)methyl]pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-[(1H-1,2,3-1riazol-1-ylacetyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-{[2-(3-hydroxypropyl)-8-methylquinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-[methyl(1H-pyrazol-1-ylacetyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-[(5-chloro-3-{2-[(dimethylamino)methyl]phenyl}quinolin-2-yl)methyl]pyrazine-2-carboxamide;3-amino-N-({2-[bis(pyridin-2-ylmethyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-({2-[bis(pyridin-3-ylmethyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-[(8-methyl-2-{3-[(1H-1,2,3-triazol-1-ylacetyl)amino]pyrrolidin-1-yl}quinolin-3-yl)methyl]pyrazine-2-carboxamide;3-amino-N-{(2-(3-{[2-(dimethylamino)-2-oxoethyl]amino}pyrrolidin-1-yl)-8-methylquinolin-3-yl]methyl}pyrazine-2-carboxamide;3-amino-N-({2-[(2-{[(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetyl](methyl)amino}ethyl)(methyl)amino]-8-methylquinolin-3-yl}methyl)pyrazine-2-carboxamide;3-amino-N-{[8-methyl-2-(methyl{2-[methyl(1H-tetrazol-1-ylacetyl)amino]ethyl}amino)quinolin-3-yl]methyl}pyrazine-2-carboxamide;3-{[3-(4-acetylpiperazin-1-yl)quinoxalin-2-y]amino}benzamide;N-methyl-N′-[(8-methyl-2-{methyl[2-(methylamino)ethyl]amino}quinolin-3-yl)methyl]cyclopropane-1,1-dicarboxamide;3-amino-N-[(8-methyl-2-{methyl[(1-methylpiperidin-2-yl)methyl]amino}quinolin-3-yl)methyl]pyrazine-2-carboxamide;N,8-dimethyl-N-[(1-methylpiperidin-2-yl)methyl]-3-[(9H-purin-6-ylamino)methyl]quinolin-2-amine;N-[(8-methyl-2-piperazin-1-ylquinolin-3-yl)methyl]-9H-purin-6-amine;N,N′-dimethyl-N-{8-methyl-3-[(9H-purin-6-ylamino)methyl]quinolin-2-yl}ethane-1,2-diamine;N-methyl-N-[2-(methyl{8-methyl-3-[(9H-purin-6-ylamino)methyl]quinolin-2-yl}amino)ethyl]2-(1H-1,2,3-triazol-1-yl)acetamide;N-{2-[{3-[(6-amino-9H-purin-9-yl)methyl]-8-methylquinolin-2-yl}(methyl)amino]ethyl}-N-methyl-2-(1H-1,2,3-triazol-1-yl)acetamide;N,8-dimethyl-N-[(1-methylpiperidin-4-yl)methyl]-3-[(9H-purin-6-ylamino)methy]quinolin-2-amine;N,8-dimethyl-N-[(1-methylpiperidin-3-yl)methyl]-3-[(9H-purin-6-ylamino)methyl]quinolin-2-amine;3-amino-N-[(8-methyl-2-{methyl[(1-methylpiperidin-4-yl)methyl]amino}quinolin-3-yl)methyl]pyrazine-2-carboxamide;3-amino-N-[(8-methyl-2-{methyl[(1-methylpiperidin-3-yl)methyl]amino}quinolin-3-yl)methyl]pyrazine-2-carboxamide;N-{3-[5-(3-aminopymzin-2-yl)-1,3,4-oxadiazol-2-yl]-8-methylquinolin-2-yl}-N,N′-dimethylethane-1,2-diamine;N-{2-[{3-[(6-amino-9H-purin-9-yl)methyl]-8-methylquinolin-2-yl}(methyl)amino]ethyl}-N-methyl-2-(1H-pyrazol-1-yl)acetamide;N[(8-methyl-2-piperidin-1-ylquinolin-3-yl)methyl]-9H-purin-6-amine;N-butyl-N,8-dimethyl-3-[(9H-purin-6-ylamino)methyl]quinolin-2-amine;N,8-dimethyl-N-[2-(methyloxy)ethyl]-3-[(9H-purin-6-ylamino)methyl]quinolin-2-amine;N,N′-dimethyl-N-[8-methyl-3-({[3-(methyloxy)phenyl]amino}methyl)quinolin-2-yl]ethane-1,2-diamine;N,N′-dimethyl-N-[8-methyl-3-({[4-(methyloxy)phenyl]oxy}methyl)quinolin-2-yl]ethane-1,2-diamine;N,N′-dimethyl-N-[8-methyl-3-({[3-(methyloxy)phenyl]oxy}methyl)quinolin-2-yl]ethane-1,2-diamine;N,N′-dimethyl-N-[8-methyl-3-(morpholin-4-ylmethyl)quinolin-2-yl]ethane-1,2-diamine;N,N′-dimethyl-N-[8-methyl-3-({[4-(methyloxy)phenyl]amino}methyl)quinolin-2-yl]ethane-1,2-diamine;N-{[2-(3,4-dihydroisoquinolin-2(1H)-yl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine;N-{[2-(2-chlorophenyl)-8-methylquinolin-3-yl]methyl}-3-(methyloxy)aniline;2-(2-chlorophenyl)-8-methyl-3-(1-{[14-(methyloxy)phenyl]oxy}ethyl)quinoline;2-(2-chlorophenyl)-8-methyl-3-({[4-(methyloxy)phenyl]oxy}methyl)quinoline;3-({]3,5-bis(methyloxy)phenyl]oxy}methyl)-2-(2-chlorophenyl)-8-metitylquinoline;9-{[2-(3,4-dihydroisoquinolin-2(1H)-yl)-8-methylquinolin-3-yl]methyl}-9H-purin-6-amine;9-{[8-methyl-2-(octahydroisoquinolin-2(1H)-yl)quinoIin-3-yl]methyl}-9H-purin-6-amine;N-{[8-methyl-2-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)quinolin-3-yl]methyl}-9H-purin-6-amine;N-{[2-(2-chlorophenyl)-8-methylquinolin-3-yl]methyl}-2-(methyloxy)aniline;N-{[2-(2-chlorophenyl)-8-methylquinolin-3-yl]methyl}-3,4-bis(methyloxy)anitine;N-{[2-(2-chlorophenyl)-8-methylquinolin-3-yl]methyl}-3,5-bis(methyloxy)aniline;3-[(1,3-benzodioxol-5-yloxy)methyl]-2-(2-chlorophenyl)-8-methylquinoline;3-({[2-chloro-4-(methyloxy)phenyl]oxy}methyl)-2-(2-chlorophenyl)-8-methylquinoline;1-[2-chlorophenyl)-8-methylquinolin-3-yl]-N-{[3-(methyloxy)phenyl]methyl}methanamine;N-{[2-(2-chlorophenyl)-8-methylquinolin-3-yl]methyl}-2,3-dihydro-1,4-benzodioxin-5-amine;3-[(6-amino-9H-purin-9-yl)methyl]-N,8-dimethyl-N-[(1-methylpiperidin-4-yl)methyl]quinolin-2-amine;3-[(6-amino-9H-purin-9-yl)methyl]-N,8-dimethyl-N-[(1-methylpiperidin-2-yl)methyl]quinolin-2-amine;3-[(6-amino-9H-purin-9-yl)methyl]-N,8-dimethyl-N-[(1-methylpyrrolidin-2-yl)methyl]quinolin-2-amine;orN,8-dimethyl-N-[(1-rnethylpiperidin-4-yl)methyl]-3-[(9H-purin-6-ylthio)methyl]quinolin-2-amine.20. A pharmaceutical formulation comprising a compound of claims 1-19admixed with a pharmaceutically acceptable carrier or excipient.
 21. Amethod of inhibiting PI3K delta comprising contacting the PI3K deltawith an effective amount of a compound of claims 1-20.
 22. A method oftreating a PI3K delta modulated disease comprising administering to amammal in need of such treatment a therapeutically effective amount of acompound of claims 1-20.
 23. A method of treating cancer diseasemediated by PI3K delta comprising administering to a mammal in need ofsuch treatment a therapeutically effective amount of a compound ofclaims 1-20.
 24. A process for making a compound of Formula II-B,comprising: (a) converting a compound of formula II-1 to a compound offormula 11-2 via reduction to the alcohol and converion of the alcoholto the the halide, wherein X¹ is halo;

(b) converting a compound of formula II-2 to a compound of formula II-3via azide formation and subsequent reduction;

(c) converting a compound of formula II-3 to a compound of formula II-4via reaction with R²-X², wherein X² is halo

(d) converting a compound of formula II-4 to a compound of formula II-Bvia reaction with CH₃NH—Y—R¹;


25. A process for making a compound of Formula II-A, comprising: (a)converting the carboxylic acid of formula II-5 to an amide of formulaII-6;

(b) converting a compound of formula II-6 to a compound of formula II-7via treatment with 2-haloacetyl chloride, wherein X¹ is halo;

(c) converting a compound of formula II-7 to a compound of formula II-8via via azide formation and subsequent reduction;

(d) converting a compound of formula II-8 to a compound of formula II-Avia reaction with R2-CO₂H;